Infertility (female)

• Infertility as a Condition
  • Affects psychological, physical, mental, spiritual, and medical aspects of patients.
  • Impacts both the patient and their partner as a couple.
  • Discussion focus: evaluation, management, and treatment of female infertility.
• Fecundability
  • Probability of achieving pregnancy in one menstrual cycle.
  • Normal fecundability understanding is essential for proper patient counseling and referrals.
  • Largest study: 85% of women conceive within 12 months.
  • Fecundability rate: 25% in the first three months, 15% for the remaining nine months.
• Timing of Assessment
  • Standard Timing(ASRM Guidelines for Infertility Evaluation):
    • Assess both male and female fertility factors at the following time points:
      • After 12 months of regular unprotected intercourse for women aged <35 years.
      • After 6 months of regular unprotected intercourse for women aged >35 years.
  • Early Assessment:
    • Warranted when clinical factors increase the risk of subfertility, such as:
      • Oligomenorrhea or Amenorrhoea: Irregular or absent menstrual cycles.
      • Known or Suspected Uterine, Tubal, or Peritoneal Disease: Conditions affecting the reproductive organs.
      • Severe Endometriosis: A condition where tissue similar to the lining inside the uterus grows outside it.
      • Multiple Surgeries to the Ovary or Loss of One Ovary: History of significant ovarian surgery.
      • Previous Chemotherapy or Radiotherapy: Treatments that can affect fertility.
      • Known or Suspected Male Subfertility: Factors indicating potential male fertility issues.

Etiology of Female Infertility

• WHO Multinational Study Findings
  • Female infertility cause in 37% of infertile couples.
  • Both male and female causes in 35% of couples.
  • Male factor infertility in 8% of couples.
• Common Identifiable Factors of Female Infertility
  • Ovulatory disorders: 25%
  • Endometriosis: 15%
  • Pelvic adhesions: 12%
  • Tubal blockage: 11%
  • Other tubal/uterine abnormalities: 11%
  • Hyperprolactinemia: 7%

Epidemiology

• Infertility Statistics:
  • Approximately 15% of couples experience infertility.
  • Infertility is defined as failure to achieve pregnancy within 12 months of regular unprotected intercourse in women aged <35 years or within six months in women aged >35 years.
• Global Infertility Rates
  • Higher rates in Eastern Europe, North Africa, and the Middle East.
  • Worldwide:
    • 2% of women aged 20 to 44 never able to have a live birth.
    • 11% with a previous live birth unable to have an additional birth.

Pathophysiology of Female Infertility

Anovulation

• Indicators of Ovulatory Cycles:
  • Regular cycle intervals of 21-35 days with consistent characteristics.
  • Presence of moliminal symptoms (cyclical symptoms like breast tenderness, mood changes).
• Confirmation of Ovulation:
  • Serum Progesterone:
    • Not required if cycles are regular in frequency and character.
    • If uncertain, measure serum progesterone in the mid-luteal phase (seven days before the next expected menses).
    • Serial progesterone levels may be necessary for patients with minor inter-cycle variation.
• Prevalence: Ovulatory disorders account for 25% of female infertility cases.
• Mechanism: Oligo-ovulation or anovulation results in no monthly oocyte release, preventing fertilization and pregnancy.
• WHO Classification of Ovulatory Disorders:
  1. Hypogonadotropic hypogonadal anovulation (e.g., hypothalamic amenorrhea)
  2. Normogonadotropic normoestrogenic anovulation (e.g., polycystic ovarian syndrome, PCOS)
  3. Hypergonadotropic hypoestrogenic anovulation (e.g., premature ovarian failure)
  4. Hyperprolactinemic anovulation (e.g., pituitary adenoma)

Type	Explanation	Result	Common Causes/Symptoms	Analogy
Hypogonadotropic Hypogonadal Anovulation (e.g., Hypothalamic Amenorrhea)	Insufficient GnRH from the hypothalamus leads to low FSH and LH from the pituitary.	Low estrogen, no ovulation.	Stress, excessive exercise, eating disorders.	Control center (hypothalamus) not sending enough commands, so the factory (ovaries) stops working.
Normogonadotropic Normoestrogenic Anovulation (e.g., Polycystic Ovarian Syndrome, PCOS)	Normal hormone signals, but ovaries fail to release mature eggs.	Irregular or absent ovulation.	Irregular periods, excess hair growth, acne.	Communication and raw materials are fine, but the machinery (ovaries) struggles to produce final product.
Hypergonadotropic Hypoestrogenic Anovulation (e.g., Premature Ovarian Failure)	High FSH and LH from the pituitary due to non-responsive ovaries, leading to low estrogen.	Premature ovarian failure.	Genetic conditions (Turner syndrome), autoimmune diseases.	The boss (pituitary gland) shouts louder (high FSH and LH) because workers (ovaries) aren’t responding.
Hyperprolactinemic Anovulation (e.g., Pituitary Adenoma)	High prolactin inhibits GnRH, reducing FSH and LH from the pituitary.	Low estrogen, no ovulation.	Pituitary tumors, irregular periods, milky discharge from breasts.	Overproduction of a disruptive element (prolactin) causes the control center (hypothalamus) to send fewer signals.

• Hypothalamic Amenorrhea (FHA):
  • Associated with eating disorders and excessive exercise.
  • Leads to decreased hypothalamic GnRH secretion due to elevated cortisol.
  • Results in decreased release of FSH and LH, causing anovulation and low estrogen levels.
  • FSH higher than LH, resembling prepubertal females.
• Polycystic Ovarian Syndrome (PCOS):
  • Accounts for 80-85% of anovulatory cases.
  • Diagnosed using Rotterdam criteria (requires 2 out of 3):
    • Oligoovulation/anovulation
    • Clinical or serological hyperandrogenism
    • Polycystic ovaries on ultrasound
  • Dysfunction in follicle development leads to anovulation.
  • Normal FSH and estrogen, variable LH.
  • High levels of anti-Mullerian hormone (AMH).
• Premature Ovarian Insufficiency (POI):
  • Hypergonadotropic hypogonadism before age 40.
  • Characterized by lack of folliculogenesis, low estrogen, and infertility.
  • Common cause: Turner syndrome (45X karyotype).
• Hyperprolactinemic Anovulation:
  • Prolactin suppresses GnRH, leading to low LH and anovulation.
  • Prolactin 20-50 ng/mL: insufficient progesterone, short luteal phase.
  • Prolactin 50-100 ng/mL: oligomenorrhea/amenorrhea.
  • Prolactin >100 ng/mL: overt hypogonadism and amenorrhea, often due to pituitary adenomas.

Endometriosis

• Definition: Endometrial tissue outside the uterine cavity.
• Prevalence: Affects 10-15% of reproductive-age women; 40-50% experience infertility.
• ASRM Stages: Minimal (I) to severe (IV).
  • Stages I-II: Inflammation (prostaglandins, cytokines, macrophages, natural killer cells).
  • Stages III-IV: Pelvic adhesions/masses, distorted anatomy.
  • Impairment of folliculogenesis, tubal function, and implantation.

Pelvic/Tubal Adhesions

• Causes: Mainly infectious processes, particularly pelvic inflammatory disease (PID).
  • PID and Chlamydia trachomatis: High risk of infertility; antibody presence inversely proportional to pregnancy rates.
  • Pregnancy rates after PID:
    • 1 episode: 89%
    • 2 episodes: 77%
    • 3 episodes: 46%
  • Livebirth rates by PID severity:
    • Mild: 90%
    • Moderate: 82%
    • Severe: 57%
• Hydrosalpinges: Tubal obstruction due to inflammation, resulting in fluid accumulation.
  • Impairs fertility by creating a hostile environment for implantation.
  • IVF patients with hydrosalpinx: 50% decrease in pregnancy rates.

Uterine Causes

• Space-Occupying Lesions: Uterine leiomyomas (fibroids).
  • Submucosal/intracavitary fibroids impair implantation and pregnancy rates.
• Congenital Uterine Abnormalities (CUA):
  • Most common: uterine septums, associated with recurrent pregnancy loss.
  • Prevalence in fertile and infertile populations is similar.
  • Account for ~8% of female infertility causes.
  • 25% of late first or second trimester miscarriages are associated with CUAs.

History and Physical

Indications for Infertility Evaluation:

• Women with unsuccessful pregnancy after:
  • 12 months of unprotected regular intercourse if under 35 years old.
  • 6 months if over 35 years old.
• Simultaneous male infertility evaluation is essential.
• Women planning to use donor sperm should undergo the same infertility workup before inseminations.

Key Aspects of History for Infertile Women:

• Duration of Infertility: How long the couple has been trying to conceive.
• Obstetrical History: Previous pregnancies and their outcomes.
• Menstrual History: Regularity, duration, and flow of menstrual cycles. , Presence of molimina (cyclical symptoms like breast tenderness, mood changes).
• Medical, Surgical, and Gynecological History: Past illnesses, surgeries, and gynecological conditions. History of sexually transmitted infections (STIs).
• Sexual History: Frequency and timing of intercourse. Male partner’s issues with erection and ejaculation.
• Social and Lifestyle History: Use of cigarettes, alcohol, and illicit drugs. Exercise, diet, and occupation.
• Family History: Genetic issues, venous thrombotic events, recurrent pregnancy loss, and infertility.

Physical Exam Components:

• Vital Signs and BMI: Measurement of blood pressure, heart rate, and body mass index.
• Thyroid Evaluation: Checking for signs of thyroid dysfunction.
• Breast Exam: Checking for galactorrhea (abnormal milk secretion).
• Signs of Androgen Excess: Dermatological examination (acne, hirsutism). Examination of external genitalia.
• Vaginal or Cervical Anatomy: Checking for abnormalities.
• Pelvic Masses or Tenderness: Palpating for masses or areas of tenderness.
• Uterine Enlargement or Irregularity: Checking for abnormalities in uterine size and shape.

Diagnostic Evaluation Categories:

1. Semen Analysis: Essential part of initial evaluation. Should be conducted before initiating treatments.
2. Assessment of Ovarian Function and Reserve:
   • Ovarian Function:
     • Menstrual Cycle History: Predictable, regular cycles with moliminal symptoms suggest ovulation.
     • Urinary LH Predictor Kits: Detect mid-cycle LH surge.
     • Progesterone Serum Level: Measure in the mid-luteal phase; >3 ng/mL indicates ovulation.
     • Ultrasound: Daily ultrasounds to follow follicle growth and disappearance (invasive and often unnecessary).
   • Ovarian Reserve – Current markers are surrogate indicators. only:
     • Cycle Day 2 FSH and Estradiol:
       • Indirect markers based on feedback inhibition of pituitary FSH secretion.
       • Significant intra- and inter-cycle variation
         • FSH: Elevated levels indicate poor ovarian response but have poor sensitivity for predicting conception.
         • E2: Simultaneous measurement increases sensitivity of FSH testing. Elevated basal E2 can indicate diminished ovarian reserve
       • FSH
         • <10 IU/mL: Likely normal ovarian reserve.
         • 10-20 IU/mL: Intermediate reserve.
         • >20 IU/mL: Poor prognosis for spontaneous ovulation.
       • Estradiol
         • <80 pg/mL: Normal reserve.
         • >100 pg/mL: 0% pregnancy rate.
     • Anti-Mullerian Hormone (AMH):
       • Produced by granulosa cells of pre-antral and antral follicles.
       • Reflects the size of the primordial follicle pool.
       • Appropriate for testing any day of the cycle.
       • Predicts ART(assisted reproductive treatment) response but not spontaneous conception.
       • Interpretation:
       • Elevated AMH: Predictive of excessive response to controlled ovarian hyperstimulation (ART(assisted reproductive treatment) _.
       • Low AMH: Predictive of poor ovarian response.
       • Poor correlation with spontaneous conception fecundity.
         • <0.5 ng/mL: Difficulty in follicle growth.
         • <1.0 ng/mL: Limited egg supply, may require aggressive induction.
         • 1.0-3.5 ng/mL: Normal values.
         • 3.5 ng/mL: Ample supply, mild induction to prevent hyperstimulation.
     • Antral Follicle Count:
       • Total number of follicles (2-10 mm) in both ovaries via transvaginal ultrasound in early follicular phase.
       • Operator-dependent. Influenced by imaging factors like machine resolution and patient body habitus. Predictive for ART response but not pregnancy.
       • Interpretation:
         • Antral follicle number >15: Predicts hyper response.
         • Antral follicle number <3-7: Predicts poor ovarian response.
         • Poor correlation with pregnancy.
3. Assessment of the Uterine Cavity:
   • transvaginal ultrasound: Identifies uterine and pelvic abnormalities that may impact fertility.
     • Allows evaluation of:
     • Antral Follicle Count (AFC).
     • Uterine anatomy and structure.
     • Mobility of pelvic organs.
   • Hysteroscopy: Gold standard for direct visualization and surgical correction of intrauterine pathology.
   • Saline Infusion Sonogram (SIS):
     • Highly sensitive and specific.
     • Adequate as a screening tool for intrauterine abnormalities.
4. Assessment of the Fallopian Tubes:
   • Laparoscopy with Chromopertubation: Gold standard for tubal patency, suspected pelvic adhesions, endometriosis, or other pathologies.
   • Hysterosalpingogram (HSG):
     • Commonly used first-line evaluation.
     • Best for detecting proximal and distal occlusions.
     • Increases pregnancy and live birth rates when using oil-soluble media.
5. Endocrinological Serum Studies:
   • Includes assessments of:
     • Follicle-stimulating hormone (FSH).
     • Luteinising hormone (LH).
     • Oestradiol (E2).
     • Thyroid-stimulating hormone (TSH).
     • Prolactin concentrations.

Preliminary fertility investigations https://www1.racgp.org.au/ajgp/2020/june/female-fertility-in-general-practice-setting

Day 2-4 follicle-stimulating hormone, luteinising hormone, oestradiol Anti-Müllerian hormone Thyroid stimulating hormone Transvaginal ultrasonography of the pelvis: – antral follicle count – pelvic anatomy and features of deep infiltrating endometriosis Blood group and antibody screen Full blood examination Rubella, varicella immunoglobulin G Hepatitis B hepatitis C human immunodeficiency virus and syphilis serology Genetic carrier screening if desired: – thalassaemia – triple screen (fragile X syndrome, cystic fibrosis, spinal muscular atrophy) – extended carrier screen

Important Notes:

• Male Partner Evaluation:
  • Critical to conduct semen analysis as part of the initial evaluation.
• PCOS Diagnosis:
  • Follow Rotterdam criteria.
  • Assess biochemical hyperandrogenism.
• Exclusion of Other Conditions:
  • Non-classical congenital adrenal hyperplasia: 17-hydroxyprogesterone concentration.
  • Cushing’s disease: Consider exclusion if severe hyperandrogenism features are present.

Preconception Screening

Essential Serology Tests:

• Rubella and Varicella Immunoglobulin G (IgG):
  • Vaccinate susceptible women prior to pregnancy.
  • Advise deferring conception for at least 28 days post-vaccination.

Additional Serology Testing:

• Hepatitis B
• Hepatitis C
• HIV
• Syphilis
  • Part of routine antenatal investigations.
  • Allows for appropriate pre-pregnancy counselling and optimization of infectious conditions to reduce maternal and fetal risk.

Genetic Carrier Screening:

• Thalassaemia Screening:
  • Full blood examination as part of routine antenatal screening.
  • Further testing (haemoglobin electrophoresis and DNA studies) based on results, family history, or high-risk ethnic group.
• Screening Panels:
  • Limited Panels: Test for spinal muscular atrophy, cystic fibrosis, and fragile X premutation.
  • Extended Panels: Test for hundreds of genetic conditions, including autosomal and X-linked recessive inheritance.
  • Counselling: Essential pre- and post-test counselling due to the high likelihood of detecting carriership for one or more conditions. Discuss the advantages and disadvantages of sequential or simultaneous screening of the couple.

Infertility Treatments

1. Lifestyle and Behavioral Modifications:

• Weight Management: Achieving a healthy BMI can improve fertility.
• Diet and Exercise: Balanced diet and regular exercise can enhance reproductive health.
• Avoiding Tobacco, Alcohol, and Illicit Drugs: Reducing or eliminating these substances can improve fertility outcomes.
• Managing Stress: Stress reduction techniques can support overall reproductive health.

2. Medications:

• Ovulation Induction Agents:
  • Clomiphene Citrate (CC): Stimulates ovulation; often used as a first-line treatment.
  • Letrozole: An alternative to Clomiphene, especially for women who do not respond to CC.
  • Gonadotropins: Hormonal injections (FSH, LH) that stimulate the ovaries to produce multiple eggs.
• Insulin Sensitizers:
  • Metformin: Often used in women with polycystic ovary syndrome (PCOS) to improve insulin sensitivity and ovulation.
• Hormonal Treatments:
  • Progesterone: Supports the luteal phase and early pregnancy.
  • Cabergoline: Used to treat high prolactin levels which can interfere with ovulation.

3. Intrauterine Insemination (IUI):

• Procedure: Sperm is washed and concentrated, then placed directly into the uterus around the time of ovulation.
• Usage: Often combined with ovulation induction agents.

4. Assisted Reproductive Technologies (ART):

• In Vitro Fertilization (IVF):
  • Procedure: Eggs are retrieved from the ovaries and fertilized with sperm in a laboratory. The resulting embryos are then transferred to the uterus.
  • Variations: Includes traditional IVF, intracytoplasmic sperm injection (ICSI), and preimplantation genetic testing (PGT).
• Intracytoplasmic Sperm Injection (ICSI):
  • Procedure: A single sperm is injected directly into an egg to facilitate fertilization.
  • Usage: Often used in cases of severe male infertility.
• Frozen Embryo Transfer (FET):
  • Procedure: Embryos that were previously frozen are thawed and transferred to the uterus.
• Donor Eggs/Sperm:
  • Usage: Used when there are significant issues with egg or sperm quality or quantity.
• Gestational Surrogacy:
  • Procedure: Another woman carries and delivers a baby for the intended parents.

Prognosis and Complications of Infertility Treatments

Pregnancy Rates per Cycle:

• No treatment: 1.3% to 3.8%
• Intrauterine Insemination (IUI) alone: 4%
• Clomiphene Citrate (CC) alone: 5.6%
• CC with IUI: 8.3%
• Gonadotropins alone: 7.7%
• Gonadotropins with IUI: 17.1%
• In Vitro Fertilization (IVF): 20.7%
• Letrozole:
  • Alone or with IUI shows similar rates as CC plus IUI.
• Transition to IVF:
  • Women who fail CC plus IUI should go directly to IVF for quicker pregnancy achievement, fewer treatment cycles, and lower costs.

Treatment Recommendations:

• Clomiphene Alone:
  • Should no longer be used as a first-line treatment for unexplained infertility.
  • Clomiphene with timed intercourse is discouraged.

Infertility Treatments Complications:

Multiple Gestations:

• Risk:
  • Higher in ART pregnancies (32%) compared to naturally conceived births (3.4%).
  • IVF fresh embryo transfer: 62% singleton, 29% twin, 3% higher-order pregnancies.
  • Oral ovarian induction agents (Clomiphene, Letrozole): Lower risk of multiples compared to gonadotropins.
  • Gonadotropins: 13% chance of multiple gestations, including triplets.
• Elective Single Embryo Transfer (eSET):
  • Recommended for good prognosis patients.
  • Reduces rates of twins and triplets to less than 1%.
  • Debate on the use of gonadotropins outside IVF protocol due to high risk of multiples.

Ectopic Pregnancy:

• Increased Risk:
  • 2-3 fold increase among infertility patients, especially with tubal factor infertility.
  • Highest risk after tubal surgery for tubal factor infertility (9-30%).
  • IVF fresh embryo transfer: Higher risk compared to frozen embryo transfer; overall rate ~1.3%.
  • Ovulation induction agents: Clomiphene (4%), Letrozole (6%), Gonadotropins (8%).

Ovarian Hyperstimulation Syndrome (OHSS):

• Signs and Symptoms:
  • Abdominal distention, nausea, vomiting, enlarged ovaries, third-spacing of fluids, renal failure, venous thrombosis, acute respiratory distress syndrome, electrolyte derangements, cardiac arrhythmias, sepsis.
  • Severe OHSS: Mortality risk if untreated.
• Risk Factors:
  • Greater than 20 mature follicles and receiving an HCG trigger shot.
  • Incidence with IVF: Moderate OHSS (6%), Severe OHSS (1%).
• Pathophysiology:
  • Increased capillary permeability leading to fluid shift into the third space.

Assessment of Fertility for Oocyte Cryopreservation(Egg Freezing)

Importance of Age:

• Age is the most important determinant of female fertility.
• Increasing trend towards delayed childbearing leading to a decrease in total fertility rate.
• Infertility is most prevalent in women aged >35 years.

Vitrification Technology:

• Cryopreserved oocytes have survival rates >84%.
• Comparable IVF outcomes to fresh oocytes.
• Increasing consideration of elective oocyte cryopreservation to allow conception of biologically related children at a later age.

Preliminary Assessment:

• Systematic History-Taking and Examination:
  • Provides valuable information on medical comorbidities.
  • Forms the basis for counselling on the risks and benefits of elective oocyte cryopreservation.
  • Expected response to controlled ovarian hyperstimulation.

Ideal Age for Oocyte Cryopreservation:

• Prior to 35 years of age.
• Poorer pregnancy outcomes associated with oocytes vitrified after 35 years due to deteriorating egg quality.