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Infertility

Infertility is the inability to conceive in the context of regular Regular Insulin 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 Ovulation The discharge of an ovum from a rupturing follicle in the ovary. Menstrual Cycle 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.

Last updated: Oct 31, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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 The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and 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 Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency 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 The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care, the female partner must be ovulatory with patent fallopian tubes Fallopian tubes The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The fallopian tubes receive an ovum after ovulation and help move it and/or a fertilized embryo toward the uterus via ciliated cells lining the tubes and peristaltic movements of its smooth muscle. Uterus, Cervix, and Fallopian Tubes: Anatomy and a receptive uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Uterus, Cervix, and Fallopian Tubes: Anatomy, 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 Gonadotropin-releasing hormone A decapeptide that stimulates the synthesis and secretion of both pituitary gonadotropins, luteinizing hormone and follicle stimulating hormone. Gnrh is produced by neurons in the septum preoptic area of the hypothalamus and released into the pituitary portal blood, leading to stimulation of gonadotrophs in the anterior pituitary gland. Puberty
FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle: follicle-stimulating hormone
LH LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle: 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 Ovulation The discharge of an ovum from a rupturing follicle in the ovary. Menstrual Cycle
    • Anovulation Anovulation Suspension or cessation of ovulation in animals or humans with follicle-containing ovaries (ovarian follicle). Depending on the etiology, ovulation may be induced with appropriate therapy. Polycystic Ovarian Syndrome: absence of ovulation Ovulation The discharge of an ovum from a rupturing follicle in the ovary. Menstrual Cycle
  • 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 Gonadotropin-releasing hormone A decapeptide that stimulates the synthesis and secretion of both pituitary gonadotropins, luteinizing hormone and follicle stimulating hormone. Gnrh is produced by neurons in the septum preoptic area of the hypothalamus and released into the pituitary portal blood, leading to stimulation of gonadotrophs in the anterior pituitary gland. Puberty (GnRH) → ↓ follicle-stimulating hormone ( FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle) → ↓ oocyte maturation → anovulation Anovulation Suspension or cessation of ovulation in animals or humans with follicle-containing ovaries (ovarian follicle). Depending on the etiology, ovulation may be induced with appropriate therapy. Polycystic Ovarian Syndrome
    • Examples:
      • Functional hypothalamic amenorrhea Functional Hypothalamic Amenorrhea Secondary Amenorrhea: due to overexercise, eating disorders, stress
      • Idiopathic Idiopathic Dermatomyositis 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 IHH Primary Amenorrhea): congenital Congenital Chorioretinitis 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 IHH Primary Amenorrhea associated with anosmia Anosmia Complete or severe loss of the subjective sense of smell. Loss of smell may be caused by many factors such as a cold, allergy, olfactory nerve diseases, viral respiratory tract infections (e.g., COVID-19), aging and various neurological disorders (e.g., Alzheimer disease). Cranial Nerve Palsies)
      • 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 Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage 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 Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast
      • Empty sella
  • Normogonadotropic normoestrogenic ovulatory dysfunction:
    • Pathophysiology: 
      • Normal GnRH and estrogens, but ↓ FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle
      • Often oligomenorrhea Oligomenorrhea Polycystic Ovarian Syndrome 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 Congenital Chorioretinitis adrenal hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation
      • Cushing syndrome Cushing syndrome A condition caused by prolonged exposure to excess levels of cortisol (hydrocortisone) or other glucocorticoids from endogenous or exogenous sources. It is characterized by upper body obesity; osteoporosis; hypertension; diabetes mellitus; hirsutism; amenorrhea; and excess body fluid. Endogenous Cushing syndrome or spontaneous hypercortisolism is divided into two groups, those due to an excess of adrenocorticotropin and those that are acth-independent. Paraneoplastic Syndromes
  • 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 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: Anatomy not responsive to FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle
      • ↑ GnRH → ↑ FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle → 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: Anatomy anovulation Anovulation Suspension or cessation of ovulation in animals or humans with follicle-containing ovaries (ovarian follicle). Depending on the etiology, ovulation may be induced with appropriate therapy. Polycystic Ovarian Syndrome
    • Example: primary ovarian insufficiency Primary ovarian insufficiency Cessation of ovarian function after menarche but before the age of 40, without or with ovarian follicle depletion. It is characterized by the presence of oligomenorrhea or amenorrhea, elevated gonadotropins, and low estradiol levels. It is a state of female hypergonadotropic hypogonadism. Etiologies include genetic defects, autoimmune processes, chemotherapy, radiation, and infections. The most commonly known genetic cause is the expansion of a cgg repeat to 55 to 199 copies in the 5′ untranslated region in the X-linked fmr1 gene. 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 Chemotherapy Osteosarcoma
      • Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma
  • 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 Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria cord-stromal tumors
      • Adrenal tumors
      • Estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy 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 FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle

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 Chlamydia Chlamydiae are obligate intracellular gram-negative bacteria. They lack a peptidoglycan layer and are best visualized using Giemsa stain. The family of Chlamydiaceae comprises 3 pathogens that can infect humans: Chlamydia trachomatis, Chlamydia psittaci, and Chlamydia pneumoniae. 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 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
    • 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 Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease:
      • 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 Implantation Endometrial implantation of embryo, mammalian at the blastocyst stage. Fertilization and First Week due to:
    • Mechanical issues
    • ↓ Endometrial receptivity
  • Causes:
    • Leiomyoma ( uterine fibroids Uterine Fibroids Gynecological Imaging) 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 Scar Dermatologic Examination tissue from prior surgery)
    • Müllerian anomalies (e.g., septate uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Uterus, Cervix, and Fallopian Tubes: Anatomy)
    • Cervical stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS)

Male etiologies and pathophysiology

Endocrine and systemic disorders:

  • Congenital Congenital Chorioretinitis/genetic causes:
    • IHH IHH Primary Amenorrhea/ 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 Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types 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 Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy disorders
    • Cushing syndrome Cushing syndrome A condition caused by prolonged exposure to excess levels of cortisol (hydrocortisone) or other glucocorticoids from endogenous or exogenous sources. It is characterized by upper body obesity; osteoporosis; hypertension; diabetes mellitus; hirsutism; amenorrhea; and excess body fluid. Endogenous Cushing syndrome or spontaneous hypercortisolism is divided into two groups, those due to an excess of adrenocorticotropin and those that are acth-independent. Paraneoplastic Syndromes
    • 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 Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens and testicular function)

Testicular defects in spermatogenesis Spermatogenesis The process of germ cell development in the male from the primordial germ cells, through spermatogonia; spermatocytes; spermatids; to the mature haploid spermatozoa. Gametogenesis:

  • 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 Motility The motor activity of the gastrointestinal tract. Gastrointestinal 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 XXY 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): 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 Testes Gonadal Hormones
  • Acquired causes:
    • Varicocele Varicocele A condition characterized by the dilated tortuous veins of the spermatic cord with a marked left-sided predominance. Adverse effect on male fertility occurs when varicocele leads to an increased scrotal (and testicular) temperature and reduced testicular volume. Varicocele, Hydrocele, and Spermatocele: 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 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 and chlamydia Chlamydia Chlamydiae are obligate intracellular gram-negative bacteria. They lack a peptidoglycan layer and are best visualized using Giemsa stain. The family of Chlamydiaceae comprises 3 pathogens that can infect humans: Chlamydia trachomatis, Chlamydia psittaci, and Chlamydia pneumoniae. Chlamydia
    • Chemotherapy Chemotherapy Osteosarcoma
    • Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma
  • Many cases are idiopathic Idiopathic Dermatomyositis.

Sperm transport and sexual dysfunction Sexual dysfunction Physiological disturbances in normal sexual performance in either the male or the female. Sexual Physiology disorders:

  • Congenital Congenital Chorioretinitis abnormalities, dysfunction, or obstruction of:
    • Epididymis Epididymis The convoluted cordlike structure attached to the posterior of the testis. Epididymis consists of the head (caput), the body (corpus), and the tail (cauda). A network of ducts leaving the testis joins into a common epididymal tubule proper which provides the transport, storage, and maturation of spermatozoa. Testicles: Anatomy
    • Vas differences
    • Ejaculatory ducts Ejaculatory Ducts Paired ducts in the human male through which semen is ejaculated into the urethra.
  • Sexual dysfunction Sexual dysfunction Physiological disturbances in normal sexual performance in either the male or the female. Sexual Physiology:
    • ED
    • Ejaculatory dysfunction

Diagnosis

Evaluation of women

Clinical:

Careful menstrual history Menstrual History Child and Adolescent Care Regular Regular Insulin cycles with molimina (cyclic breast tenderness and ovulatory pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways) strongly suggest ovulation Ovulation The discharge of an ovum from a rupturing follicle in the ovary. Menstrual Cycle.

Laboratory tests:

  • Cycle day 3 FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle, LH LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle, and estradiol Estradiol The 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. Noncontraceptive Estrogen and Progestins:
    • FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle with ↓ estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy functional hypothalamic amenorrhea Functional Hypothalamic Amenorrhea Secondary Amenorrhea
    • LH LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle: FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle ratio > 2 with normal estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy 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 FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle with ↓ estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy → POI
    • FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle with ↑ estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy → estrogen-secreting tumor Tumor Inflammation
  • Cycle day 21 progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones: ↑ progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones in the luteal phase Luteal phase The period in the menstrual cycle that follows ovulation, characterized by the development of corpus luteum, increase in progesterone production by the ovary and secretion by the glandular epithelium of the endometrium. The luteal phase begins with ovulation and ends with the onset of menstruation. Menstrual Cycle confirms ovulation Ovulation The discharge of an ovum from a rupturing follicle in the ovary. Menstrual Cycle
  • Anti-Müllerian hormone ( AMH AMH A glycoprotein that causes regression of mullerian ducts. It is produced by sertoli cells of the testes. In the absence of this hormone, the mullerian ducts develop into structures of the female reproductive tract. In males, defects of this hormone result in persistent mullerian duct, a form of male pseudohermaphroditism. Primary Amenorrhea):
    • Ovarian reserve test
    • AMH AMH A glycoprotein that causes regression of mullerian ducts. It is produced by sertoli cells of the testes. In the absence of this hormone, the mullerian ducts develop into structures of the female reproductive tract. In males, defects of this hormone result in persistent mullerian duct, a form of male pseudohermaphroditism. Primary Amenorrhea → POI
  • Other hormonal abnormalities that contribute to ovulatory dysfunction:
    • Prolactin Prolactin A lactogenic hormone secreted by the adenohypophysis. It is a polypeptide of approximately 23 kd. Besides its major action on lactation, in some species prolactin exerts effects on reproduction, maternal behavior, fat metabolism, immunomodulation and osmoregulation. Breasts: Anatomy 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
    • Thyroid-stimulating hormone Thyroid-stimulating hormone A glycoprotein hormone secreted by the adenohypophysis. Thyrotropin stimulates thyroid gland by increasing the iodide transport, synthesis and release of thyroid hormones (thyroxine and triiodothyronine). Thyroid Hormones 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
    • Testosterone Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens 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: Anatomy
    • Ovarian tumors
  • Saline infusion sonogram Sonogram Chorioretinitis (SIS):
    • Injection of saline into the uterine cavity to distend it during sonography Sonography The visualization of deep structures of the body by recording the reflections or echoes of ultrasonic pulses directed into the tissues. Use of ultrasound for imaging or diagnostic purposes employs frequencies ranging from 1. 6 to 10 megahertz. Diagnostic Procedures in Gynecology 
    • To diagnose polyps, uterine septa, synechiae
  • Hysterosalpingogram:
    • Inject dye into the uterine cavity under fluoroscopy Fluoroscopy Production of an image when x-rays strike a fluorescent screen. X-rays.
    • Bilateral “fill and spill” of dye confirms tubal patency.
    • Some uterine anomalies may be visible.

Surgery:

  • Hysteroscopy Hysteroscopy Endoscopic examination, therapy or surgery of the interior of the uterus. Diagnostic Procedures in Gynecology:
    • 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 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 and some pelvic adhesions

Evaluation of men

Semen analysis:

Table: Normal parameters in semen analysis
Volume 1.5–5.0 mL
pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance > 7.2
Viscosity < 3
Sperm concentration > 15 million/mL
Total sperm count > 40 million/mL
Percent motility Motility The motor activity of the gastrointestinal tract. Gastrointestinal Motility > 40%
Forward progression > 2 (based on a scale Scale Dermatologic Examination from 0 to 4)
Normal morphology > 4% normal
Round cells < 5 million/mL
Sperm agglutination < 2

Laboratory and imaging if semen analysis is abnormal:

  • FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle, LH LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle, and morning total testosterone Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens:
    • FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle and LH LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle with ↓ testosterone Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens → 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 FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle and LH LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle with ↓ testosterone Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens → 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 Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types defects)
    • Normal FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle with ↑ LH LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle and testosterone Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens → partial androgen resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing
    • ↓↓ LH LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle with ↑ muscle mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast → suspect androgen abuse
  • Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies (if abnormalities are suspected):
    • Karyotype Karyotype The full set of chromosomes presented as a systematized array of metaphase chromosomes from a photomicrograph of a single cell nucleus arranged in pairs in descending order of size and according to the position of the centromere. Congenital Malformations of the Female Reproductive System 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 Cystic Fibrocystic Change fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans transmembrane conductance regulator (CFTR) mutations → cystic Cystic Fibrocystic Change fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans
  • Scrotal and transrectal ultrasound: dilated seminal vesicles Seminal vesicles A saclike, glandular diverticulum on each ductus deferens in male vertebrates. It is united with the excretory duct and serves for temporary storage of semen. → obstruction of ejaculatory ducts Ejaculatory Ducts Paired ducts in the human male through which semen is ejaculated into the urethra.

Management

Lifestyle factors

  • Coital frequency of every 1–2 days around ovulation Ovulation The discharge of an ovum from a rupturing follicle in the ovary. Menstrual Cycle
  • Smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases cessation
  • Limit Limit A value (e.g., pressure or time) that should not be exceeded and which is specified by the operator to protect the lung Invasive Mechanical Ventilation excessive alcohol and caffeine Caffeine A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine’s most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. Stimulants intake.
  • Fertility-friendly lubricants (many common brands inhibit sperm motility Motility The motor activity of the gastrointestinal tract. Gastrointestinal Motility)
  • Weight loss Weight loss Decrease in existing body weight. Bariatric Surgery in the case of 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 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 Ovulation The discharge of an ovum from a rupturing follicle in the ovary. Menstrual Cycle induction, ovarian hyperstimulation, and insemination

  • Requirements:
    • 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: Anatomy capable of normal function
    • Patent tubes
    • Sperm
  • Letrozole Letrozole A triazole and benzonitrile derivative that is a selective non-steroidal aromatase inhibitor, similar to anastrozole. It is used in the treatment of metastatic or locally advanced breast cancer in postmenopausal women. Antiestrogens:
    • Aromatase Aromatase An enzyme that catalyzes the desaturation (aromatization) of the ring a of C19 androgens and converts them to C18 estrogens. In this process, the 19-methyl is removed. This enzyme is membrane-bound, located in the endoplasmic reticulum of estrogen-producing cells of ovaries, placenta, testes, adipose, and brain tissues. Aromatase is encoded by the cyp19 gene, and functions in complex with NADPH-ferrihemoprotein reductase in the cytochrome p450 system. Adipose Tissue: Histology inhibitor that ↓ estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy → ↓ pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types inhibition → ↑ FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle
    • Used in normogonadotropic normoestrogenic ovulatory dysfunction
    • Not FDA approved, but considered as 1st-line therapy
    • ↓ Rate of twins compared with clomiphene citrate Clomiphene citrate A triphenyl ethylene stilbene derivative which is an estrogen agonist or antagonist depending on the target tissue. Antiestrogens
  • Clomiphene citrate Clomiphene citrate A triphenyl ethylene stilbene derivative which is an estrogen agonist or antagonist depending on the target tissue. Antiestrogens:
    • Selective estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors modulator → ↓ pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types inhibition → ↑ FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle
    • Used in normogonadotropic normoestrogenic ovulatory dysfunction
    • Classic treatment still used, but no longer 1st line
  • Injectable gonadotropins (e.g., FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle):
    • 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-sensitizing agents: 
      • Metformin Metformin A biguanide hypoglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. Non-insulinotropic Diabetes Drugs
      • Used in overweight patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with 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 resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing 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 Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS agonists:
      • Bromocriptine Bromocriptine A semisynthetic ergotamine alkaloid that is a dopamine D2 agonist. It suppresses prolactin secretion. Parkinson’s Disease Drugs
      • Cabergoline
      • Used to ↓ prolactin Prolactin A lactogenic hormone secreted by the adenohypophysis. It is a polypeptide of approximately 23 kd. Besides its major action on lactation, in some species prolactin exerts effects on reproduction, maternal behavior, fat metabolism, immunomodulation and osmoregulation. Breasts: Anatomy levels in 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
  • Intrauterine insemination (IUI)
    • Injection of a processed semen sample into the uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Uterus, Cervix, and Fallopian Tubes: Anatomy
    • Often combined with ovulation Ovulation The discharge of an ovum from a rupturing follicle in the ovary. Menstrual Cycle induction to ↑ pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care rates
Assisted reproductive technology process

Intrauterine insemination

Image: “ Assisted reproductive technology Assisted Reproductive Technology Clinical and laboratory techniques used to enhance fertility in humans and animals. Reproductive Ethical Issues 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 Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with:
    • Failed ovulation Ovulation The discharge of an ovum from a rupturing follicle in the ovary. Menstrual Cycle induction/IUI
    • Severe tubal disease
    • Advanced age
  • Procedure:
    • Oocytes Oocytes Female germ cells derived from oogonia and termed oocytes when they enter meiosis. The primary oocytes begin meiosis but are arrested at the diplotene state until ovulation at puberty to give rise to haploid secondary oocytes or ova (ovum). Ovaries: Anatomy are surgically retrieved using ultrasound guidance.
    • 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 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 Endometrium The mucous membrane lining of the uterine cavity that is hormonally responsive during the menstrual cycle and pregnancy. The endometrium undergoes cyclic changes that characterize menstruation. After successful fertilization, it serves to sustain the developing embryo. Embryoblast and Trophoblast Development.
  • Additional options often combined with IVF:
    • ICSI:
      • Injection of a single sperm into a retrieved oocyte
      • Used in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with abnormal sperm motility Motility The motor activity of the gastrointestinal tract. Gastrointestinal Motility or morphology

Other fertility options

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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