Stat Consult: Infertility in Women

Background

Infertility is the inability to conceive after 1 year of frequent unprotected sexual intercourse
It occurs in approximately 15% of reproductive-aged couples worldwide and is more common in developing countries
Causes of infertility may be multifactorial and include:
- Combined male and female factors in about 40%
- Male factor infertility in about 26%-30%
- Ovulation disorders in about 21%-25%
- Tubal factors in about 14%-20%
- Cervical/uterine/peritoneal disorders in about 10%-13%
- Idiopathic in about 25%-28%
Diagnosis usually based on history and physical; both partners are evaluated concurrently

Pathogenesis in Women

Ovulation disorder infertility
- Occurs when ovaries fail to produce a mature oocyte on a regular basis due to hypothalamic dysfunction, polycystic ovary syndrome (PCOS), ovarian failure, and/or hyperprolactinemia
Tubal factor infertility occurs when fallopian tubes fail to capture ovulated ova and/or transport sperm and embryo due to:
- Pelvic inflammatory disease (PID) and/or sexually transmitted disease (STD)
- Endometriosis associated with retrograde menstruation of debris from uterus
- Scarring from abdominal or pelvic surgery
- Occlusion of cornua and interstitial portion of fallopian tube due to leiomyoma
- Pelvic tuberculosis associated with salpingitis
Uterine factor infertility occurs when uterus fails to allow embryo to implant and/or fails to support normal embryonic growth and development due to:
- Congenital uterine anomalies
- Endometrial polyps
- Intrauterine synechiae with adhesion of myometrium to opposing uterine wall
- Uterine leiomyomas
Cervical factor infertility occurs when cervix fails to capture or transport sperm into uterus and fallopian tubes due to reduced cervical mucus quality/quantity or cervical conization

History and Physical Examination

Infertility history
- Duration of infertility
- Menstrual history
- Sexual activity, including frequency and timing (in relation to cycle) of coitus
- Previous contraceptive method (especially intrauterine device)
Past medical history
- Previously abnormal pap smears
- Exposure to sexually transmitted disease
- Endocrine disorders
- Endometriosis, PID
- PCOS or primary ovarian insufficiency
- Pelvic tuberculosis
- Fibroids
- Chemotherapy or pelvic radiation
- Genetic disorders (Turner syndrome)
- Previous pregnancies/outcomes
- Prior pelvic/abdominal surgeries

Physical
- Measure height/weight
- Evaluate skin – hirsutism (acne on face and/or chest may indicate hyperandrogenism); vitiligo may indicate autoimmune systemic disease
- Assess for thyroid abnormalities
- Assess for breast changes
- Examine abdomen for organomegaly, ascites, surgical scars
Perform pelvic exam, assess for:
- Vaginal, cervical, or adnexal abnormality
- Size, shape, mobility, and position of uterus
- Nodules or tenderness in posterior cul-de-sac (may indicate endometriosis/tuberculosis)

Diagnosis

Infertility evaluation is indicated
- After 1 year of frequent unprotected sexual intercourse for women < 35 years old without known risk factors for infertility
- After 6 months of frequent unprotected intercourse in couples with woman aged > 35 years and/or in couples with known clinical cause or predisposing factors for infertility
- Immediately in women > 40 years old, or if there is an obvious cause for infertility/subfertility

Initial evaluation to assess ovulatory function
- Midluteal serum progesterone level (> 6 ng/mL on day 21 of a 28-day menstrual cycle indicates ovulation)
- Urinary luteinizing hormone assessment via urinary ovulation kit
- Basal body temperature charting is no longer considered a reliable indicator of ovulation, and is not recommended for evaluating ovulation
Assessment of tubal patency
- Hysterosalpingography (HSQ) and hysterosalpingo-contrast sonography (HYCOSY) may aid in diagnosis of recurrent pregnancy loss/infertility
- Laparoscopy and chromotubation may detect tubal patency or proximal/distal tubal occlusive disease

Testing ovarian reserve
- Assessment of follicle stimulating hormone (FSH) and estradiol levels on cycle day 2-4
- Clomiphene (clomid) citrate challenge test may help predict ability to achieve clinical pregnancy through infertility treatment
- Serum antimüllerian hormone levels may help predict response to gonadotrophin stimulation in women with in vitro fertilization (IVF)
Testing for suspected uterine abnormalities
- Hysteroscopy considered definitive method for diagnosis and treatment
- HSG and HYCOSY or saline infusion sonohistography (SIS)
Testing for suspected pelvic abnormalities
- Transvaginal ultrasound may help detect endometriomas and pelvic/adnexal adhesions
- Laparoscopy may be indicated to confirm diagnosis in women with inconclusive results on less-invasive tests
Other testing includes
- Serum thyroid stimulating hormone (TSH)
- Prolactin level
Endometrial biopsy not indicated for detection of luteal phase deficiency

Management

Treatment of infertility is based on the underlying cause
- For anovulation (WHO has classified anovulation into groups)
  - WHO Group I: hypogonadotropic hypogonadism (hypothalamic pituitary failure):
    - If BMI is < 19, advise weight gain and/or exercise moderation
    - First-line treatment includes ovulation induction with gonadotropins with luteinizing hormone activity or pulsatile administration of gonadotropin-releasing hormone
    - Second-line treatment is IVF
  - WHO Group II: normogonadotropic normoestrogenic anovulation (PCOS):
    - Weight loss may improve pregnancy outcomes if BMI is ≥ 30.
    - First-line treatment includes ovulation induction with clomiphene, metformin, or both
    - Second-line treatment may include laparoscopic ovarian drilling or ovulation induction with gonadotropins
    - Third-line treatment is IVF
  - WHO Group III: hypergonadotropic hypoestrogenic anovulation (primary ovarian insufficiency), first-line therapy is IVF with donated oocytes
- For hyperprolactinemic amenorrhea, treatment includes therapy with dopamine agonists (such as bromocriptine or cabergoline)
- For fallopian tube disorders:
  - Tubal microsurgery or laparoscopic tubal surgery may restore tubal patency in patients with mild tubal disease
    - For patients with hydrosalpinx, consider laparoscopic salpingectomy prior to IVF
- For amenorrhea and intrauterine adhesions, offer hysteroscopic adhesiolysis to restore normal menstruation and increase the likelihood of conception
- For endometriosis-associated infertility, options include surgery or assisted reproductive technology (ART)
- For idiopathic infertility:
  - Advise patients to try to conceive naturally for 2 years; to increase chance of conception:
    - Regular unprotected intercourse (2-3 times/week) near the time of ovulation
  - Intercourse on multiple days during the fertile window (5 days preceding and the day of ovulation)
- Consider IVF after 2 years of failed expectant management
- Intrauterine insemination (IUI) should not be routinely offered to patients with idiopathic infertility
Ovarian hyperstimulation syndrome (OHSS)
- Reported in about 1.4% of all IVF cycles
- Considered the most serious complication resulting from controlled ovarian hyperstimulation in ART
- Symptoms range from mild abdominal distension to organ failure or death

Prognosis

Probability of conception in fertile women < 40 years old and with regular, unprotected sexual intercourse:
- 20%-25% per reproductive cycle
- 60% within first 6 months
- 84% within 1 year
- 92% within 2 years
Factors associated with increased chance of conception in women with infertility
- Short duration of infertility
- Previous fertility
- Age < 40 years
- Ideal body mass index (> 19 and < 30)
About 50% overall pregnancy rate following treatment for infertility
- 5% after timed intercourse
- 10% after superovulation with IUI
- 15%-25% after ART

Fertility preservation

In patients being treated for cancer
- Consider oocyte/embryo cryopreservation in adolescents/patients of reproductive age at risk for infertility due to planned cancer treatments in cases when patients are well enough to undergo ovarian stimulation/oocyte collection
- Consider ovarian tissue cryopreservation for patients requiring emergent chemotherapy or radiotherapy (allowing no time for oocyte stimulation and retrieval)

Kendra Church, MS, PA-C, is a physician assistant at Dana-Faber Cancer Institute/Brigham & Women’s Hospital and is also an Associate Deputy Editor for DynaMed, an evidence-based point-of-care database.

Sources

National institute for Health Care Excellence. Fertility problems: assessment and treatment. Updated September, 2017. Accessed June 29, 2022. https://www.nice.org.uk/guidance/cg156
O’Flynn Norma. Assessment and treatment for people with fertility problems: Nice guideline. Br J Gen Pract. 2014;64(618):50-51. doi: 10.3399/bjgp14X676609
Kamel RM. Management of the infertile couple: an evidence-based protocol. Reprod Biol Endocrinol. 2010;8:21. doi:10.1186/1477-7827-8-21
Lindsay TJ, Vitrikas KR. Evaluation and treatment of infertility. Am Fam Physician. 2015;91(5):308-314; Correction. Am Fam Physician. 2015;92(6):437.
Danis P. Natural procreative technology for treating infertility. Am Fam Physician. 2015;92(8):668.
Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: a committee opinion. Fertil Steril. 2015;103(6):e44-e50. doi:10.1016/j.fertnstert.2015.03.019

Topics:

Fertility Infertility Obstetrics and Gynecology Pregnancy Reproductive Medicine Women's Health