Infertility

Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Diagnosis of infertility involves laboratory assessments for ovulatory function and a hysterosalpingogram to determine tubal patency in women, and semen analysis to assess the condition in men. Management involves treatment of the underlying pathology when possible, and may include ovulation induction with either timed intercourse or intrauterine insemination (IUI), in vitro fertilization (IVF), and donor gametes, or by gestational surrogates or adoption.

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Definition and Epidemiology

Definition

Infertility is defined as the inability of a couple to conceive after 12 months of regular intercourse, in cases when the woman is < 35 years of age, or after 6 months of regular intercourse in couples when the woman is > 35 years of age.

Epidemiology

  • Normal fecundability (the probability that a cycle will result in a pregnancy):
    • 25% in the 1st 3 months
    • 15% in the 4th to 12th months
    • Approximately 80%–90% of healthy couples will conceive within 12 months.
  • Prevalence of primary infertility in women:
    • 15–34 years of age: 7%–9%
    • 35–39 years of age: 25%
    • 40–44 years of age: 30%

Etiology and Pathophysiology

To achieve pregnancy, the female partner must be ovulatory with patent fallopian tubes and a receptive uterus, whereas the male partner must be able to produce sperm that is capable of fertilizing the oocyte.

Etiologies of couples

  • Female factor alone: 37%
  • Male factor alone: 8%
  • Both female and male factors: 35%
  • Unexplained infertility: 5%
  • Exact etiologies often difficult to determine unless absolute infertility factors are present (e.g., bilateral tubal obstruction).
  • Couples often have more than 1 contributing etiology.
Etiologies of infertility in couples (left) and women (right)

Etiologies of infertility in couples (left) and in women (right)

Image by Lecturio. License: CC BY-NC-SA 4.0

Female etiologies and pathophysiology

Causes of infertility in women can be categorized as ovulatory dysfunction, tubal factors, and uterine factors. 

Hypothalamic-pituitary-ovarian (HPO) axis review:

The hypothalamus-pituitary-ovarian

Hypothalamus-pituitary-ovarian (HPO) axis
GnRH: gonadotropin-releasing hormone
FSH: follicle-stimulating hormone
LH: luteinizing hormone

Image by Lecturio. License: CC BY-NC-SA 4.0

Ovulatory dysfunction:

Normal hormonal fluctuations throughout the menstrual cycle

Normal hormonal fluctuations throughout the menstrual cycle

Image by Lecturio. License: CC BY-NC-SA 4.0
  • Types of dysfunction:
    • Oligoovulation: infrequent ovulation
    • Anovulation: absence of ovulation
  • Hypogonadotropic hypogonadism: 
    • Pathophysiology:
      • Hypothalamus is not functioning properly.
      • ↓ Gonadotropin-releasing hormone (GnRH) → ↓ follicle-stimulating hormone (FSH) → ↓ oocyte maturation → anovulation
    • Examples:
      • Functional hypothalamic amenorrhea: due to overexercise, eating disorders, stress
      • Idiopathic hypogonadotropic hypogonadism (IHH): congenital deficiency of GnRH, such as in Kallmann syndrome (IHH associated with anosmia)
      • Sheehan syndrome: hypopituitarism caused by ischemia during postpartum hemorrhage
      • Infiltrative disease (e.g., sarcoidosis)
      • Sellar mass
      • Empty sella
  • Normogonadotropic normoestrogenic ovulatory dysfunction:
    • Pathophysiology: 
      • Normal GnRH and estrogens, but ↓ FSH
      • Often oligomenorrhea and ↑ androgens
    • Examples:
      • Polycystic ovary syndrome (PCOS)
      • Nonclassical congenital adrenal hyperplasia
      • Cushing syndrome
  • Hypergonadotropic hypogonadism:
    • Pathophysiology
      • Ovaries not responsive to FSH
      • ↑ GnRH → ↑ FSH → nonresponsive ovaries → anovulation
    • Example: primary ovarian insufficiency (POI)
      • Turner syndrome
      • FMR1 permutation
      • Autoimmune
      • Chemotherapy
      • Radiation
  • Other etiologies of ovulatory dysfunction:
    • Oocyte aging
    • Hyperprolactinemia
    • Hypothyroidism
    • Estrogen- or androgen-secreting tumors: 
      • Sex cord-stromal tumors
      • Adrenal tumors
      • ↑ Estrogen or androgens → ↓ FSH

Tubal factors:

  • Prevent sperm from reaching the egg due to:
    • Occlusion (usually from adhesions)
    • Inflammation
  • Causes:
    • Pelvic inflammatory disease: caused by chlamydia or gonorrhea
    • Hydrosalpinges
    • Endometriosis: fertility challenges due to both tubal adhesions and inflammation
    • Prior tubal surgery
    • Prior ectopic pregnancy
    • Nontubal infections:
      • Appendicitis
      • Inflammatory bowel disease
      • Pelvic TB

Uterine factors:

  • Impaired implantation due to:
    • Mechanical issues
    • ↓ Endometrial receptivity
  • Causes:
    • Leiomyoma (uterine fibroids) that impinge on uterine cavity
    • Endometrial polyps
    • Synechiae (scar tissue from prior surgery)
    • Müllerian anomalies (e.g., septate uterus)
    • Cervical stenosis

Male etiologies and pathophysiology

Endocrine and systemic disorders:

  • Congenital/genetic causes:
    • IHH/Kallmann syndrome
    • Genetic defects affecting gonadotropins
  • Acquired conditions leading to hypothalamic or pituitary dysfunction:
    • Sellar masses
    • Infiltrative disease (e.g., sarcoidosis)
    • Hyperprolactinemia (e.g., medications)
    • Thyroid disorders
    • Cushing syndrome
    • Hormone-secreting tumors
  • Systemic illness
  • Obesity (can ↓ testosterone and testicular function)

Testicular defects in spermatogenesis:

  • Definitions:
    • Azoospermia: no sperm in the ejaculate
    • Oligozoospermia: ↓ sperm count 
      • In 80% of infertile men 
      • The most common cause of infertility in men
    • Asthenozoospermia: ↓ sperm motility
    • Teratozoospermia: ↑ number of sperm with abnormal morphology
  • Genetic causes:
    • Klinefelter syndrome (47,XXY): one of the most common causes of primary hypogonadism in men
    • Y microdeletions
    • Cryptorchidism: undescended testes
  • Acquired causes:
    • Varicocele: dilation of the pampiniform plexus
    • Infection: 
      • Mumps
      • TB
      • Leprosy
      • Gonorrhea and chlamydia
    • Chemotherapy
    • Radiation
  • Many cases are idiopathic.

Sperm transport and sexual dysfunction disorders:

  • Congenital abnormalities, dysfunction, or obstruction of:
    • Epididymis
    • Vas differences
    • Ejaculatory ducts
  • Sexual dysfunction:
    • ED
    • Ejaculatory dysfunction

Diagnosis

Evaluation of women

Clinical:

Careful menstrual history: Regular cycles with molimina (cyclic breast tenderness and ovulatory pain) strongly suggest ovulation.

Laboratory tests:

  • Cycle day 3 FSH, LH, and estradiol:
    • ↓ FSH with ↓ estrogen → functional hypothalamic amenorrhea
    • LH:FSH ratio > 2 with normal estrogen → PCOS
    • ↑ FSH with ↓ estrogen → POI
    • ↓ FSH with ↑ estrogen → estrogen-secreting tumor
  • Cycle day 21 progesterone: ↑ progesterone in the luteal phase confirms ovulation
  • Anti-Müllerian hormone (AMH):
    • Ovarian reserve test
    • ↓ AMH → POI
  • Other hormonal abnormalities that contribute to ovulatory dysfunction:
    • ↑ Prolactin → hyperprolactinemia
    • ↑ Thyroid-stimulating hormone → hypothyroidism
    • ↑ Testosterone → PCOS

Imaging:

  • Ultrasound:
    • Antral follicle count (assessment of ovarian reserve)
    • Leiomyomas
    • Polycystic-appearing ovaries
    • Ovarian tumors
  • Saline infusion sonogram (SIS):
    • Injection of saline into the uterine cavity to distend it during sonography 
    • To diagnose polyps, uterine septa, synechiae
  • Hysterosalpingogram:
    • Inject dye into the uterine cavity under fluoroscopy.
    • Bilateral “fill and spill” of dye confirms tubal patency.
    • Some uterine anomalies may be visible.

Surgery:

  • Hysteroscopy:
    • An alternative to SIS 
    • Allows for simultaneous diagnosis and treatment
  • Laparoscopy with chromopertubation 
    • Inject dye through tubes to assess patency.
    • Allows for assessment and treatment of endometriosis and some pelvic adhesions

Evaluation of men

Semen analysis:

  • Volume
  • pH
  • Concentration
  • Count
  • Motility
  • Morphology
  • Leukocyte count
  • Agglutination
Table: Normal parameters in semen analysis
Volume1.5–5.0 mL
pH> 7.2
Viscosity< 3
Sperm concentration> 15 million/mL
Total sperm count> 40 million/mL
Percent motility> 40%
Forward progression> 2
Normal morphology> 4% normal
Round cells< 5 million/mL
Sperm agglutination< 2

Laboratory and imaging if semen analysis is abnormal:

  • FSH, LH, and morning total testosterone:
    • ↑ FSH and LH with ↓ testosterone → hypergonadotropic hypogonadism (testicular defects)
    • Normal or ↓ FSH and LH with ↓ testosterone → hypogonadotropic hypogonadism (hypothalamic or pituitary defects)
    • Normal FSH with ↑ LH and testosterone → partial androgen resistance
    • ↓↓ LH with ↑ muscle mass → suspect androgen abuse
  • Genetic testing (if abnormalities are suspected):
    • Karyotype → Klinefelter syndrome
    • Y-chromosome microdeletions
    • Cystic fibrosis transmembrane conductance regulator (CFTR) mutations → cystic fibrosis
  • Scrotal and transrectal ultrasound: dilated seminal vesicles → obstruction of ejaculatory ducts

Management

Lifestyle factors

  • Coital frequency of every 1–2 days around ovulation
  • Smoking cessation
  • Limit excessive alcohol and caffeine intake.
  • Fertility-friendly lubricants (many common brands inhibit sperm motility)
  • Weight loss in the case of obesity or in overweight women
  • Weight gain for women who are underweight
  • Reduce environmental toxins: pesticides, cleaning solvents, and heavy metals

Surgical correction of uterine anomalies

  • Fibroids
  • Polyps
  • Synechiae
  • Septa

Ovulation induction, ovarian hyperstimulation, and insemination

  • Requirements:
    • Ovaries capable of normal function
    • Patent tubes
    • Sperm
  • Letrozole:
    • Aromatase inhibitor that ↓ estrogen → ↓ pituitary inhibition → ↑ FSH
    • Used in normogonadotropic normoestrogenic ovulatory dysfunction
    • Not FDA approved, but considered as 1st-line therapy
    • ↓ Rate of twins compared with clomiphene citrate
  • Clomiphene citrate:
    • Selective estrogen receptor modulator → ↓ pituitary inhibition → ↑ FSH
    • Used in normogonadotropic normoestrogenic ovulatory dysfunction
    • Classic treatment still used, but no longer 1st line
  • Injectable gonadotropins (e.g., FSH):
    • High risk of multiples, including higher-order multiples
    • Used in egg retrieval prior to in vitro fertilization (IVF) and hypothalamic hypogonadism
    • Requires monitoring with frequent ultrasound procedures
  • Other medical treatments:
    • Insulin-sensitizing agents: 
      • Metformin
      • Used in overweight patients with insulin resistance and PCOS in combination with other ovulation-inducing agents
    • Dopamine agonists:
      • Bromocriptine
      • Cabergoline
      • Used to ↓ prolactin levels in hyperprolactinemia
  • Intrauterine insemination (IUI)
    • Injection of a processed semen sample into the uterus
    • Often combined with ovulation induction to ↑ pregnancy rates
Assisted reproductive technology process

Intrauterine insemination

Image: “Assisted reproductive technology process” by BruceBlaus. License: CC BY 3.0

In vitro fertilization

  • For patients with:
    • Failed ovulation induction/IUI
    • Severe tubal disease
    • Advanced age
  • Procedure:
    • Oocytes are surgically retrieved using ultrasound guidance.
    • Fertilization occurs via:
      • Introduction of sperm from a semen sample
      • Intracytoplasmic sperm injection (ICSI) 
    • Embryos are cultivated in a Petri dish and reimplanted into the endometrium.
  • Additional options often combined with IVF:
    • Preimplantation genetic diagnosis (PGD): screening of blastocysts for euploidy or a specific genetic defect prior to reimplantation
    • ICSI:
      • Injection of a single sperm into a retrieved oocyte
      • Used in patients with abnormal sperm motility or morphology

Other fertility options

  • Donor gametes (eggs or sperm)
  • Donor embryos
  • Gestational carriers
  • Adoption

References

  1. Schorge, J.O., Schaffer, J.I., et al. (2008). Williams Gynecology (1st ed. pp. 426-467).
  2. Practice Committee of the American Society for Reproductive Medicine. (2008). Definitions of infertility and recurrent pregnancy loss. Fertil Steril. 90(5 Suppl), S60 https://pubmed.ncbi.nlm.nih.gov/19007647/ 
  3. Kuohung, W., Hornstein, M.D. (2020). Overview of infertility. In Eckler, K. (Ed.), UpToDate. Retrieved February 7, 2021, from https://www.uptodate.com/contents/overview-of-infertility
  4. Kuohung, W., Hornstein, M.D. (2020). Causes of female infertility. In Eckler, K. (Ed.), UpToDate. Retrieved February 7, 2021, from https://www.uptodate.com/contents/causes-of-female-infertility 
  5. Kuohung, W., Hornstein, M.D. (2020). Evaluation of female infertility. In Eckler, K. (Ed.), UpToDate. Retrieved February 7, 2021, from https://www.uptodate.com/contents/evaluation-of-female-infertility
  6. Hornstein, M.D., Gibbons, W.E., Schenken, R.S. (2020). Optimizing natural fertility in couples planning pregnancy. In Eckler, K. (Ed.), UpToDate. Retrieved February 7, 2021, from https://www.uptodate.com/contents/optimizing-natural-fertility-in-couples-planning-pregnancy
  7. Anawalt, B.D., Page, S.T. (2019). Approach to the male with infertility. In Martin, K.A. (Ed.), UpToDate. Retrieved February 7, 2021, from https://www.uptodate.com/contents/approach-to-the-male-with-infertility 
  8. Anawalt, B.D., Page, S.T. (2020). Causes of male infertility. In Martin, K.A. (Ed.), UpToDate. Retrieved February 7, 2021, from https://www.uptodate.com/contents/causes-of-male-infertility

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