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 Fertilization To undergo fertilization, the sperm enters the uterus, travels towards the ampulla of the fallopian tube, and encounters the oocyte. The zona pellucida (the outer layer of the oocyte) deteriorates along with the zygote, which travels towards the uterus and eventually forms a blastocyst, allowing for implantation to occur. Fertilization and First Week (IVF), and donor gametes, or by gestational surrogates or adoption.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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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 Probability Probability is a mathematical tool used to study randomness and provide predictions about the likelihood of something happening. There are several basic rules of probability that can be used to help determine the probability of multiple events happening together, separately, or sequentially. Basics of Probability that a cycle will result in a pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care):
    • 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 Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care, 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 Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. 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 Menstrual cycle The menstrual cycle is the cyclic pattern of hormonal and tissular activity that prepares a suitable uterine environment for the fertilization and implantation of an ovum. The menstrual cycle involves both an endometrial and ovarian cycle that are dependent on one another for proper functioning. There are 2 phases of the ovarian cycle and 3 phases of the endometrial cycle. Menstrual Cycle

Image by Lecturio. License: CC BY-NC-SA 4.0
  • Types of dysfunction:
    • Oligoovulation: infrequent ovulation
    • Anovulation: absence of ovulation
  • Hypogonadotropic hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism
    • Pathophysiology:
      • Hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. 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 Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism (IHH): congenital deficiency of GnRH, such as in Kallmann syndrome Kallmann syndrome Kallmann syndrome (KS), also called olfacto-genital syndrome, is a genetic condition that causes hypogonadotropic hypogonadism due to decreased secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus. The lack of sex hormones results in impaired pubertal development. Kallmann Syndrome (IHH associated with anosmia)
      • Sheehan syndrome: hypopituitarism Hypopituitarism Hypopituitarism is a condition characterized by pituitary hormone deficiency. This condition primarily results from a disease of the pituitary gland, but it may arise from hypothalamic dysfunction. Pituitary tumors are one of the most common causes. The majority of cases affect the anterior pituitary lobe (adenohypophysis), which accounts for 80% of the gland. Hypopituitarism caused by ischemia during postpartum hemorrhage Postpartum hemorrhage Postpartum hemorrhage is one of the most common and deadly obstetric complications. Since 2017, postpartum hemorrhage has been defined as blood loss greater than 1,000 mL for both cesarean and vaginal deliveries, or excessive blood loss with signs of hemodynamic instability. Postpartum Hemorrhage
      • Infiltrative disease (e.g., sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis)
      • Sellar mass
      • Empty sella
  • Normogonadotropic normoestrogenic ovulatory dysfunction:
    • Pathophysiology: 
      • Normal GnRH and estrogens, but ↓ FSH
      • Often oligomenorrhea and ↑ androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens
    • Examples:
      • Polycystic ovary syndrome ( PCOS PCOS Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of reproductive-age women, affecting nearly 5%-10% of women in the age group. It is characterized by hyperandrogenism, chronic anovulation leading to oligomenorrhea (or amenorrhea), and metabolic dysfunction. Polycystic Ovarian Syndrome)
      • Nonclassical congenital adrenal hyperplasia Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) consists of a group of autosomal recessive disorders that cause a deficiency of an enzyme needed in cortisol, aldosterone, and androgen synthesis. The most common subform of CAH is 21-hydroxylase deficiency, followed by 11β-hydroxylase deficiency. Congenital Adrenal Hyperplasia
      • Cushing syndrome
  • Hypergonadotropic hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism:
    • Pathophysiology
      • Ovaries not responsive to FSH
      • ↑ GnRH → ↑ FSH → nonresponsive ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries → anovulation
    • Example: primary ovarian insufficiency Primary ovarian insufficiency Primary ovarian insufficiency (POI) is a condition resulting from the depletion or dysfunction of the ovarian follicles, leading to cessation of ovulation and menses before age 40. Primary ovarian insufficiency is primarily idiopathic. Patients present with signs and symptoms of menopause prior to age 40, including oligo- or amenorrhea, vaginal dryness (often leading to dyspareunia), and infertility. Primary Ovarian Insufficiency (POI)
      • Turner syndrome Turner syndrome Turner syndrome is a genetic condition affecting women, in which 1 X chromosome is partly or completely missing. The classic result is the karyotype 45,XO with a female phenotype. Turner syndrome is associated with decreased sex hormone levels and is the most common cause of primary amenorrhea. Turner Syndrome
      • FMR1 permutation
      • Autoimmune
      • Chemotherapy
      • Radiation
  • Other etiologies of ovulatory dysfunction:
    • Oocyte aging
    • Hyperprolactinemia Hyperprolactinemia Hyperprolactinemia is defined as a condition of elevated levels of prolactin (PRL) hormone in the blood. The PRL hormone is secreted by the anterior pituitary gland and is responsible for breast development and lactation. The most common cause is PRL-secreting pituitary adenomas (prolactinomas). Hyperprolactinemia
    • Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism
    • Estrogen- or androgen-secreting tumors: 
      • Sex cord-stromal tumors
      • Adrenal tumors
      • ↑ Estrogen or androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens → ↓ FSH

Tubal factors:

  • Prevent sperm from reaching the egg due to:
    • Occlusion (usually from adhesions)
    • Inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
  • Causes:
    • Pelvic inflammatory disease Pelvic inflammatory disease Pelvic inflammatory disease (PID) is defined as a polymicrobial infection of the upper female reproductive system. The disease can affect the uterus, fallopian tubes, ovaries, and adjacent structures. Pelvic inflammatory disease is closely linked with sexually transmitted diseases, most commonly caused by Chlamydia trachomatis, Neisseria gonorrhoeae, and Gardnerella vaginalis. Pelvic Inflammatory Disease: caused by chlamydia or gonorrhea Gonorrhea Gonorrhea is a sexually transmitted infection (STI) caused by the gram-negative bacteria Neisseria gonorrhoeae (N. gonorrhoeae). Gonorrhea may be asymptomatic but commonly manifests as cervicitis or urethritis with less common presentations such as proctitis, conjunctivitis, or pharyngitis. Gonorrhea
    • Hydrosalpinges
    • Endometriosis Endometriosis Endometriosis is a common disease in which patients have endometrial tissue implanted outside of the uterus. Endometrial implants can occur anywhere in the pelvis, including the ovaries, the broad and uterosacral ligaments, the pelvic peritoneum, and the urinary and gastrointestinal tracts. Endometriosis: fertility challenges due to both tubal adhesions and inflammation
    • Prior tubal surgery
    • Prior ectopic pregnancy Ectopic pregnancy Ectopic pregnancy refers to the implantation of a fertilized egg (embryo) outside the uterine cavity. The main cause is disruption of the normal anatomy of the fallopian tube. Ectopic Pregnancy
    • Nontubal infections:
      • Appendicitis Appendicitis Appendicitis is the acute inflammation of the vermiform appendix and the most common abdominal surgical emergency globally. The condition has a lifetime risk of 8%. Characteristic features include periumbilical abdominal pain that migrates to the right lower quadrant, fever, anorexia, nausea, and vomiting. Appendicitis
      • Inflammatory bowel disease
      • Pelvic TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis

Uterine factors:

  • Impaired implantation due to:
    • Mechanical issues
    • ↓ Endometrial receptivity
  • Causes:
    • Leiomyoma (uterine fibroids) that impinge on uterine cavity
    • Endometrial polyps Endometrial polyps Endometrial polyps are pedunculated or sessile projections of the endometrium that result from overgrowth of endometrial glands and stroma around a central vascular stalk. Endometrial polyps are a few millimeters to a few centimeters in size, can occur anywhere within the uterine cavity, and, while usually benign, can be malignant, particularly in postmenopausal women. 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 Kallmann syndrome Kallmann syndrome (KS), also called olfacto-genital syndrome, is a genetic condition that causes hypogonadotropic hypogonadism due to decreased secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus. The lack of sex hormones results in impaired pubertal development. Kallmann Syndrome
    • Genetic defects affecting gonadotropins
  • Acquired conditions leading to hypothalamic or pituitary dysfunction:
    • Sellar masses
    • Infiltrative disease (e.g., sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis)
    • Hyperprolactinemia Hyperprolactinemia Hyperprolactinemia is defined as a condition of elevated levels of prolactin (PRL) hormone in the blood. The PRL hormone is secreted by the anterior pituitary gland and is responsible for breast development and lactation. The most common cause is PRL-secreting pituitary adenomas (prolactinomas). Hyperprolactinemia (e.g., medications)
    • Thyroid disorders
    • Cushing syndrome
    • Hormone-secreting tumors
  • Systemic illness
  • Obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. 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 Klinefelter syndrome Klinefelter syndrome is a chromosomal aneuploidy characterized by the presence of 1 or more extra X chromosomes in a male karyotype, most commonly leading to karyotype 47,XXY. Klinefelter syndrome is associated with decreased levels of testosterone and is the most common cause of congenital hypogonadism. Klinefelter Syndrome (47,XXY): one of the most common causes of primary hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism in men
    • Y microdeletions
    • Cryptorchidism Cryptorchidism Cryptorchidism is one of the most common congenital anomalies in young boys. Typically, this asymptomatic condition presents during a routine well-child examination where 1 or both testicles are not palpable in the scrotum. Cryptorchidism: undescended testes
  • Acquired causes:
    • Varicocele: dilation of the pampiniform plexus
    • Infection: 
      • Mumps Mumps Mumps is caused by a single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae. Mumps is typically a disease of childhood, which manifests initially with fever, muscle pain, headache, poor appetite, and a general feeling of malaise, and is classically followed by parotitis. Mumps Virus/Mumps
      • TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis
      • Leprosy Leprosy Leprosy, also known as Hansen's disease, is a chronic bacterial infection caused by Mycobacterium leprae complex bacteria. Symptoms primarily affect the skin and peripheral nerves, resulting in cutaneous manifestations (e.g., hypopigmented macules) and neurologic manifestations (e.g., loss of sensation). 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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of 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 PCOS Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of reproductive-age women, affecting nearly 5%-10% of women in the age group. It is characterized by hyperandrogenism, chronic anovulation leading to oligomenorrhea (or amenorrhea), and metabolic dysfunction. Polycystic Ovarian Syndrome
    • ↑ 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 PCOS Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of reproductive-age women, affecting nearly 5%-10% of women in the age group. It is characterized by hyperandrogenism, chronic anovulation leading to oligomenorrhea (or amenorrhea), and metabolic dysfunction. Polycystic Ovarian Syndrome

Imaging:

  • Ultrasound:
    • Antral follicle count (assessment of ovarian reserve)
    • Leiomyomas
    • Polycystic-appearing ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). 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 Laparoscopy Laparoscopy is surgical exploration and interventions performed through small incisions with a camera and long instruments. Laparotomy and 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
Volume 1.5–5.0 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 Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism (testicular defects)
    • Normal or ↓ FSH and LH with ↓ testosterone → hypogonadotropic hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. 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 Klinefelter syndrome Klinefelter syndrome is a chromosomal aneuploidy characterized by the presence of 1 or more extra X chromosomes in a male karyotype, most commonly leading to karyotype 47,XXY. Klinefelter syndrome is associated with decreased levels of testosterone and is the most common cause of congenital hypogonadism. Klinefelter Syndrome
    • Y-chromosome microdeletions
    • Cystic fibrosis Cystic fibrosis Cystic fibrosis is an autosomal recessive disorder caused by mutations in the gene CFTR. The mutations lead to dysfunction of chloride channels, which results in hyperviscous mucus and the accumulation of secretions. Common presentations include chronic respiratory infections, failure to thrive, and pancreatic insufficiency. 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 Fertilization To undergo fertilization, the sperm enters the uterus, travels towards the ampulla of the fallopian tube, and encounters the oocyte. The zona pellucida (the outer layer of the oocyte) deteriorates along with the zygote, which travels towards the uterus and eventually forms a blastocyst, allowing for implantation to occur. Fertilization and First Week (IVF) and hypothalamic hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism
    • Requires monitoring with frequent ultrasound procedures
  • Other medical treatments:
    • Insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin-sensitizing agents: 
      • Metformin
      • Used in overweight patients with insulin resistance and PCOS PCOS Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of reproductive-age women, affecting nearly 5%-10% of women in the age group. It is characterized by hyperandrogenism, chronic anovulation leading to oligomenorrhea (or amenorrhea), and metabolic dysfunction. Polycystic Ovarian Syndrome 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 Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care rates
Assisted reproductive technology process

Intrauterine insemination

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

In vitro fertilization Fertilization To undergo fertilization, the sperm enters the uterus, travels towards the ampulla of the fallopian tube, and encounters the oocyte. The zona pellucida (the outer layer of the oocyte) deteriorates along with the zygote, which travels towards the uterus and eventually forms a blastocyst, allowing for implantation to occur. Fertilization and First Week

  • 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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