REPD 372 Module 5 Content PDF

1.1 SECTION 01: BASIC CONCEPTS AND STATISTICS OF INFERTILITY The concept of fertility is tightly associated with reproductive function. Any abnormalities in the structure or functions of the reproductive system can impair reproductive capacity. In this section, you will learn the relevant clinical...

1.1 SECTION 01: BASIC CONCEPTS AND STATISTICS OF INFERTILITY The concept of fertility is tightly associated with reproductive function. Any abnormalities in the structure or functions of the reproductive system can impair reproductive capacity. In this section, you will learn the relevant clinical terminology surrounding fertility and infertility, discuss how reproductive problems can lead to infertility, and explore some of the global statistics on fertility trends and infertility issues and learn about why these are important aspects in the study of fertility. 1.2 DEMOGRAPHIC TERMS FOR FERTILITY Before you dive into this module, it is important to understand the differences between some of the key terms that you will see in this section. **Fertility:** The natural capability to produce offspring. A related term, fecundity, is the potential output of reproduction by an organism, as measured by number of gametes, seeds, etc. **Fertility Rate:** Total fertility rate (TFR) in simple terms refers to total number of children born or likely to be born to a woman in her lifetime if she were subject to the prevailing rate of age-specific fertility in the population. **Birth Rate:** The total number of live births per 1,000 in a population in a year or period. 1.3 STATISTICS ON INFERTILITY More than 186 million people worldwide suffer from infertility, with 8-12% of couples of reproductive age worldwide affected by infertility. Both males and females experience infertility. Roughly 1/3 of infertility cases can be attributed to either male or female factors, while the remaining 2/3 of cases are attributed to both or have no known cause. Infertility is more prevalent in developing countries. The estimated prevalence of infertility in developing nations is one in every four couples, whereas in developed nations, it is one in every seven couples. Age-related fertility decline affects both men and women but begins earlier in women. Above age 37, female fertility rates decline steeply, while sperm count decreases significantly around age 40. Other factors including lifestyle and environmental factors are believed to play an increasingly significant role with age. 1.4 WHY IT MATTERS: FERTILITY AND POPULATION DYNAMICS The study of fertility is a key factor in informing national and even global policies, which then influence a variety of. Examples of these topics include reproductive research, healthcare, family planning, child development, and social support for the aging population. A correct understanding of population dynamics is vital for making decisions in health policy and resource allocation. **Population dynamics:** A branch of life sciences that studies the size and age composition of populations, and the biological and environmental processes driving them. Fertility rates tend to be higher in developing countries due to the lack of access to contraceptives, poor maternity care, and generally lower levels of female education. Conversely, developed countries tend to have lower fertility rates due to lifestyle choices associated with economic affluence where mortality rates are low, birth control is easily accessible, and children often can be seen as an economic drain caused by housing, education, and other costs involved in bringing up children. Also, women often prioritize education and careers, resulting in delayed childbearing. 1.6 WHY IT MATTERS: FERTILITY AND POPULATION DYNAMICS AROUND THE WORLD Upon examination of the graph, it is evident that over the past 50 years, there has been an overall decline in fertility rates across the world. The global fertility rate is now 2.5 children per woman. However, this average masks the underlying regional variations. Europe has the lowest fertility rate with 1.6 children per woman, while Africa has the highest fertility rate with 4.7 children per woman. This decline in global fertility rates has been attributed mainly to modernization. 1.7 WHY IT MATTERS: FERTILITY AND POPULATION DYNAMICS IN CANADA Over the past 150 years, Canada in particular has seen a decline in fertility, as women are having fewer children overall and at increasing maternal ages. The total fertility rate in Canada has been below the replacement level-fertility for over 40 years. This decline has resulted in a demographic shift that has changed the country\'s population structure, from a relatively young and growing population to an aging population, which in turn, results in social and legislative changes. The graph shows a decline in fertility rate in Canada, from 3.5 in the 1921 down to 1.4 in 2016. Note that the current fertility rate of 1.4 is well below the replacement-level fertility of 2.1. **Total fertility rate:** The average number of children born per woman. **Replacement level-fertility:** The total fertility rate at which a population exactly replaces itself from one generation to the next, without migration. 1.8 CLINICAL TERMINOLOGY FOR FERTILITY The period of time when a couple is trying to have a child is often the first time that they begin to think about their ability to conceive. Because of this, fertility issues often go undetected and undiagnosed until this period. There are several key clinical terms that define fertility. **Fertility:** defined as the capacity to establish a clinical pregnancy within 12 months of regular and unprotected sexual intercourse. **Subfertility**: general term used to describe any form of reduced fertility with a prolonged time to achieve conception in a couple. **Infertility**: incapacity to establish a clinical pregnancy after 12 months of regular and unprotected sexual intercourse, often due to potentially treatable causes. **Sterility:** often used interchangeably with infertility, but refers to a complete incapacity to conceive naturally. For example, due to the absence of gonads regardless of cause (congenital, injury, etc.). 1.9 TYPES OF INFERTILITY There are 2 clinical types of infertility: primary infertility and secondary infertility. **Primary Infertility**: couples who have not become pregnant after a minimum of 1 year of sexual intercourse without using birth control methods. **Secondary Infertility:** couples who have previously carried a pregnancy to term, but are now are unable to conceive. Secondary infertility is the most common form of female infertility around the globe, and is most common in regions of the world with high rates of unsafe abortion and poor maternity care, due to the high rates of post-abortive and postpartum infections. 1.11 FACTORS THAT INFLUENCE INFERTILITY In general, the evaluations and tests used to diagnose infertility will examine the hormones, gametes, gonads, reproductive ducts, and external genitalia. Any factor that negatively affects any of these components will have a negative impact on fertility. Diagnostic tests and fertility interventions are based on our knowledge of the factors and mechanisms behind impaired reproductive function. You will explore these mechanisms in upcoming sections. **Hormones:** Circulating levels of the regulatory hormones of the reproductive system. **Gametes:** Quantity and quality of oocytes in females, and sperm in males. **Gonads:** Anatomy and function of ovaries or testes. **Reproductive ducts:** Anatomy and function of the reproductive ducts in male and female. **External genitalia**: Anatomy and function of the external genitalia. 1.12 THE PROCESS OF DIAGNOSING INFERTILITY If a couple has not achieved a pregnancy after 12 months of regular unprotected intercourse, a diagnostic exam is recommended. **Medical History:** The medical exams begin by exploring the patient's medical history. This allows doctors to identify previous factors that may have caused the patient's current fertility issues, as well as current factors that may be contributing as well, such as the existence of a previous or current medical condition, previous injuries or surgeries, and even behavioral factors such as levels of physical activity, current medications, smoking habit, alcohol consumption, or drug use. **Physical Exam** A physical exam evaluates more specific anatomical and physiological factors. These include the presence of structural abnormalities in the external genitalia and reproductive tract and the appearance of secondary sex characteristics. Performing blood analyses and additional tests allows doctors to detect hormonal imbalances and other potential metabolic abnormalities. 1.13 EVALUATION OF MEDICAL HISTORY In both males and females, a clinician will first review an individual's medical history to identify any factors that may directly or indirectly be contributing to impaired reproductive function. - Previous physical injuries that may have compromised the integrity of the reproductive tract - Previous infections such as sexually transmitted infections (S T Is), urinary tract infections, and others - Current systemic diseases such as hypertension, diabetes, and autoimmune conditions - Current hormonal conditions, such as hypogonadism and polycystic ovary syndrome (PCOS) - Current lifestyle factors, such as nutrition, physical activity, medication use, smoking habit, or drug use - Other serious conditions that may impair reproductive capacity, such as cancer (ovarian, prostate), or uterine fibroids, among others 1.14 SPECIFIC DIAGNOSTIC TESTS Now that you have a general understanding of how the different components of the reproductive system relate to fertility, we will take a look at specific tests that can be conducted in both males and females to evaluate fertility during a physical exam. Males - Semen Analysis: Used to detect sperm abnormalities such as azoospermia. - Testicular Biopsy: Used as a diagnostic tool to determine unexplained male infertility as well as azoospermia. - Imaging: A pelvic and scrotal ultrasound or MRI. Both - Physical Exam: An examination of testes and penis or an examination of breasts, genitals, and pelvis. - Hormonal Tests: Mainly F S H and either testosterone or progesterone. - Genetic Testing: To diagnose certain genetic disorders affecting fertility. Females - Imaging: Generally a hysterosalpingography to check for uterine or tubal abnormalities, or pelvic ultrasound to visualize the ovaries and follicles. **Azoospermia:** A condition where semen contains no sperm. 1.15 IDIOPATHIC INFERTILITY Despite the available tests, sometimes clinicians are still unable to identify the cause of infertility. This is known as idiopathic infertility. A diagnosis of idiopathic infertility does not preclude the possibility for treatment. Depending on the health status of the person, clinicians will sometimes proceed through treatment, and a successful pregnancy might be achieved. 2.1 SECTION 02: CAUSES OF INFERTILITY Infertility can be caused by a variety of natural or environmental factors, or a combination of both. Understanding the underlying causes of infertility allows clinicians to provide targeted and more effective care, and helps researchers develop new interventions to continue improving our approach to the treatment of fertility issues. In this section you will learn about the factors that cause or contribute to infertility. You will explore five broad factors that can affect reproductive dysfunction and will discuss how they can lead to impaired fertility. 2.2 CAUSES OF INFERTILITY Infertility can be caused by a number of natural (intrinsic) and environmental (extrinsic) factors. Although our bodies constantly respond to external influences, intrinsic factors generally encompass physiological changes that are not a direct result of an external factor. For instance, a congenital anomaly that disrupts reproductive function would be an intrinsic factor, since the person was born with it. Conversely, a physical injury affecting a reproductive organ would be an extrinsic factor, as it was acquired at some point throughout that person\'s life. There are a vast number of factors that can affect fertility, so in this section, you will learn a few selected representative factors and explore how they can impair reproductive function and fertility. 2.2.1 CONGENITAL DISORDERS AND FERTILITY Infertility can be caused by a number of congenital conditions. You should know from previous modules that there are numerous congenital disorders that involve reproductive abnormalities, such as Klinefelter syndrome and Turner's Syndrome. There are also congenital anatomical anomalies such as anorchia or cryptorchidism. Each of these will negatively impact fertility depending on the aspects of reproductive function that are being negatively affected. Such conditions are usually detected at an early age and become part of an individual\'s medical history, which would be considered during a diagnostic evaluation. **Congenital:** A disease or condition that is present at birth. **Anorchia:** A condition in which a genetic male is born without testes. **Cryptorchidism:** A condition in which one or both of the testes fail to descend from the abdomen into the scrotum during prenatal development. 2.2.1.1 TURNER'S SYNDROME Turner's Syndrome is one of the most common causes of gonadal dysgenesis. It is a condition in which a female is partially or completely missing one of her X chromosomes (45, X0). In addition to under-developed ovaries and altered secondary sexual characteristics, classical Turner's features include short stature, webbing of the neck, widely spaced nipples, cardiac and renal abnormalities, and often hormonal imbalances among many other health issues. **Gonadal Dysgenesis:** Any congenital developmental disorder in which there is abnormal development of the gonads in males or females. Most females with Turner's syndrome are infertile due to ovarian failure. Only 2% of the women with Turner's syndrome have natural pregnancies. However, these pregnancies have high rates of miscarriages, stillbirths, and malformed babies. There have been successful interventions with oocyte donation programs, but even these carry a high rate of miscarriage due to uterine factors. 2.2.1.2 KLINEFELTER SYNDROME Klinefelter syndrome is a genetic disorder in which boys are born with an extra X chromosome (47,XXY). This genetic condition causes hypogonadism in males, causing reduced sperm count, and is one of the common genetic causes of infertility in men. Klinefelter syndrome is usually diagnosed by evaluating the outward symptoms (e.g. small testes, tall/slender build, and low testosterone), and confirmed by chromosome analysis, also known as karyotyping. 2.2.3 FERTILITY AND THE AGING PROCESS Aging is considered the most important natural factor associated with fertility decline in both males and females. Aging is a natural (intrinsic) process that involves the progressive deterioration and decline in normal functioning of all bodily systems, and the reproductive system is no exception. However, although aging is a natural process, it is modulated by external factors such as diet, exercise, drug use, among other factors, that can influence the rate and the direction of decline. As such, aging could be considered an ongoing process that underlies all other processes in the body. In the case of the reproductive system, there are specific age-related changes to reproductive function that directly impact fertility. Recall from Module 2 that females are born with all the oocytes they will produce in their lifetime, meaning that the number of oocytes available for ovulation is in decline starting from birth. The extended period of time that oocytes/follicles wait in dormancy combined with their progressive decline in number are factors that are thought to contribute to the accumulation of errors over time and the functional decline of the ovary. 2.2.5 FEMALE FERTILITY AND MENOPAUSE In females, reproductive aging involves a decline in reproductive potential, mainly due to a decline in ovarian function. This involves the gradual decrease in the quantity and quality of oocyte/follicles, and alterations in hormonal signaling that eventually lead to the cessation of ovarian follicular activity and the menstrual cycle. The cessation of the cycle is known as menopause, but the process occurs gradually over a period of several years, typically in females who are between 45-55 years of age. A slight decline in fertility can be detected as early as 25 years of age, but clinically significant decline starts to become detectable around 30 years of age, with a more pronounced decline each year after. After age 45, symptoms of the altered function of the aging ovaries start to become evident in regularly menstruating women. **Menopause:** The point at which a woman no longer has menstrual periods, and the ovaries have stopped producing most of their estrogen and releasing eggs. It is diagnosed when a woman has missed 12 consecutive periods. 2.2.5.1 MENOPAUSE TIMELINE **Menopause:** Defined as one year of spontaneous missed periods without any abnormality or drugs that can alter menstrual cycles. **Premenopause:** Years from puberty to menopause, also referred to as the reproductive life of a female. **Postmenopause:** a stage which begins with the last menstrual period and continues for the rest of a woman's life. **Perimenopause:** starts before menopause and continues 12 months after it. In this stage the body begins to undergo several physical and hormonal changes. **Premature menopause:** Spontaneous cessation of menses before age 40 years is called premature menopause, or premature ovarian failure. Certain interventions such a radiation therapy or oophorectomy (surgical removal of ovaries) can result in permanent cessation of ovarian function and, thus, induce an artificial menopause. 2.2.6 THE IMPACT OF MENOPAUSE ON FOLLICLE QUANTITY Recall from Module 2 that on average, females have approximately 400,000 primordial follicles at the beginning of puberty. About 300 to 400 follicles reach maturity during the female reproductive lifespan, while the rest of the follicles are lost by apoptosis, a process that continues even during periods when there is no ovulation, such as pregnancy, breastfeeding or use of oral contraceptives. This follicular pool declines progressively with increasing age, as does the ovarian reserve. The ovarian reserve depends on both the follicular pool, and the health and quality of the oocytes contained in the pool. Although the exact mechanisms of this decline are not well understood, the decline is accelerated in the last 10-15 years before menopause due to hormonal dysregulation. **Follicular Pool:** The number of extra follicles available for maturation. **Ovarian Reserve:** The capacity of the ovaries to produce an oocyte capable of fertilization and pregnancy. 2.2.7 THE HORMONAL CHANGES RELATED TO MENOPAUSE **Increased sensitivity to GnRH** With the continual loss of the remaining follicles, there is a decrease in the production of gonadotropin surge inhibiting factor (GnSIF), resulting in a higher sensitivity of the pituitary to gonadotropin releasing hormone and a subsequent rise in luteinizing hormone (LH). **Less suppression of FSH secretion** The earliest hormonal change associated with menopause involves a rise in follicle stimulating hormone (FSH), which is attributed to a decreased production of inhibin B and antimullerian hormone (AMH). Increasing FSH levels accelerate the processes of selection and recruitment of the dominant follicles, which speeds up the loss of the remaining follicles. Overall, the increase in these gonadotropins results in a decrease in number and quality of the remaining follicles, and thus a decrease in the ovarian production of estrogen and progesterone. **Inhibin B:** A glycoprotein hormone that is produced by mature follicles and suppresses the release of FSH. **Antimullerian hormone (AMH):** A glycoprotein hormone that is produced by mature follicles and suppresses the release of FSH. 2.2.8 MENOPAUSE AND OOCYTE QUALITY Oocyte quality decreases significantly with age, likely due to the accompanying increase in oxidativestress. This decrease in oocyte quality can be detected starting around 35 years of age, as measured by the presence of chromosomal abnormalities. Consequently, the risk of experiencing pregnancy complications due to embryo abnormalities also increases significantly at around 35 years of age, with complications such as preterm delivery, and spontaneous miscarriage becoming more likely. 2.2.8.1 THE ROLE OF OXIDATIVE STRESS One of the major processes associated with the process of aging is oxidative stress. Oxidative stress is a physiological imbalance in the production of reactive oxygen species (ROS), ROS are natural byproducts of metabolism which, due to their high chemical reactivity, cause cellular damage by oxidizing, and thus, altering cellular DNA, fatty acids, and proteins. As the systems that counteract oxidative damage become less efficient over time, the accumulated damage can expand to become a condition or disease. **Lifestyle Factors** Oxidative stress can also be significantly worsened by lifestyle choices such as unhealthy diet, sedentarism, smoking, alcohol intake, and drug use, which is why lifestyle factors are important for health. **Fertility** In both males and females oxidative stress is considered to be a major factor in the process of natural fertility decline. It is also known to play an important role in the development of aging- related diseases, such as atherosclerosis, hypertension, diabetes mellitus, ischemic diseases, and neurodegeneration, among other conditions, that can indirectly affect reproductive function. 2.2.9 MALE FERTILITY AND THE AGING PROCESS Just as with female fertility, male fertility declines with age. In average healthy men, age-related fertility decline starts to become evident around 40 years of age, much later than in females. Older age is associated with a progressive decline in reproductive capacity in men, largely due to declining testosterone levels. In males, this progressive hormone decline is known as andropause or late-onset hypogonadism. The process is much slower than menopause in females, and it is also not well understood. Although symptoms of andropause vary, they commonly include: - Low sex drive - Lack of energy - Difficulty getting erections and/or weaker erections - Loss of muscles mass or strength - Increased body fat - Depression and/or mood swings - Hot flashes 2.2.10 AGING AND ERECTILE DYSFUNCTION The earliest and most common symptom of male fertility decline is a decrease in erectile function. Erectile dysfunction (ED) affects 10% of men at age 40 years and 80% over the age of 70 years. In about 40% of men over 50 years old, the primary cause of erectile dysfunction is related to atherosclerotic disease, which affects circulation. Other potential causes include psychological, neurological, hormonal, pharmacological, and anatomical factors. Through the use of pharmacotherapy, men with ED may be able to engage in sexual intercourse, and therefore have the opportunity to conceive. If this does not prove to be successful, they can turn to some of the reproductive technologies you will learn about in Section 3. 2.2.11 THE IMPACT OF HORMONES ON MALE FERTILITY Regulation of the HPG axis in men is altered with age. Serum testosterone levels are known to decline with age particularly due to the decrease in the number of the Leydig cells, deterioration of testicular perfusion, and disturbances to GnRH and chorionic gonadotropin secretion. Testosterone levels decline with aging at the rate of 1% per year and this decline is more pronounced in free testosterone levels because of alterations in sex hormone binding globulin (SHBG). 2.2.11.1 HYPOGONADISM AND AGING Testosterone deficiency due to a testicular defect is known as primary hypogonadism. When testosterone deficiency is caused by a problem with the pituitary gland or hypothalamus, it is called secondary hypogonadism. In this case, testes are normal but their function is impaired due to abnormal signaling from the brain, such as, reduced gonadotropin secretion. In addition, other parameters such as body weight, lifestyle, and acute and chronic diseases play a role in the alteration of the HPG axis with age. 2.2.12 THE IMPACT OF AGING ON THE TESTES As men grow older, testicular function and metabolism deteriorate as the testes undergo age-related morphological changes such as a decrease in the number of germ cells, Leydig and Sertoli cells, as well as structural changes, including the narrowing of the seminiferous tubules. These changes are associated with the onset of primary testicular failure, a decline in testosterone secretion caused by a deficiency or absence of Leydig cell function. **Gametes** Sperm morphology is affected by aging, with the percentage of sperm with normal morphology decreasing after the age of 40. This is likely because of an increase in replication errors, causing DNA mutations and fragmentation in sperm cells. Sperm volume, motility, and morphology are also known to decrease with aging. **Ducts and Glands** Prostate enlargement in older men, known as benign prostatic hyperplasia (B P H), is one of the most common age-related diseases in men. After the age of 45, semen volume gradually decreases due to the functional decline of accessory glands. Daily sperm production also declines with age, with men over 50 experiencing decreases greater than 30%. 2.2.13 WHY IT MATTERS: DOWN'S SYNDROME Age contributes to fertility decline in both males and females, with females experiencing symptoms at an earlier age. Children born to older parents (i.e. over the age of 35) are at greater risk for genetic abnormalities, such as Down syndrome. Down syndrome, also known as Trisomy 21, is the most common chromosomal disorder. \\ This study used registry data of 3,419 cases of Down's syndrome collected over a 15 year period. As depicted in the graph, the rate of Down syndrome steeply increased with maternal age 35 to 39. When paternal age was taken into account, the rate of Down syndrome decreased, demonstrating that maternal age is the major contributor as has been well established. However, it is also evident that the paternal effect is greatest in couples older than 40 years, and there is no increase in the rate of Down syndrome in couples younger than 35. 2.2.14 FERTILITY AND PHYSICAL INJURY There are a number of physical injuries that can affect reproductive function, whether directly or indirectly. **Direct Injury** In a direct injury, the integrity of the reproductive structures is compromised, potentially resulting in permanent impairment of function depending on the severity of the injury. Genital injuries are an example of a direct injury. They are much more common in males, due to the anatomy of the genitalia and external location of the testes. Injury to the testes can destroy the structure of the seminiferous tubules, eliminating the capacity for sperm production. In the case of a serious injury affecting both testes, testosterone replacement may be necessary to compensate for the loss of the gonads. In Females, the internal location of the ovaries and less exposed genitalia make serious injuries rare. A much more common problem is vaginal or uterine prolapse after childbirth, which occurs when the pelvic floor muscles and ligaments weaken to the point of losing the ability to support these organs in place. **Indirect Injury** An indirect injury would involve an injury to a non-reproductive structure that ends up interfering with normal reproductive function. An injury can occur suddenly, such as those that occur in an accident, but they can also appear progressively, due to degeneration caused by a disease or condition. The impact of an indirect injury can be less obvious, but equally or more severe. For example, a spinal cord injury (SCI) involves any damage to the spinal cord that results in functional changes below the injury. We will discuss how an S C I can affect reproductive function in the next slide. 2.2.15 SPINAL CORD INJURY AND THE REPRODUCTIVE SYSTEM Spinal cord injuries (SCI) can significantly impair sexual and reproductive function. Aside from the loss of mobility of the legs, an SCI can affect a variety of systems in the body depending on the severity and location of injury, which will determine which nerves become compromised. By now you should know the innervation of the reproductive organs, as covered in Module 3. Sexual function can be affected by an injury as low as the last vertebra (S5). The severity of the effect on sexual and reproductive functions will depend on the severity and site of injury, which means that an SCI can affect fertility. However, the impact of an SCI on fertility is significantly different between males and females. 2.2.16 SCI AND MALE FERTILITY In males, fertility is tightly associated with sexual function. If the principal reproductive organ, the penis, and its normal erectile function are impaired, it becomes impossible for a male to conceive without medical assistance. Thus, the impact of an SCI on men\'s fertility occurs via its effects on genital innervation. Recall from Module 3 penile innervation is derived from the autonomic nervous system, using both sympathetic and parasympathetic nerves for involuntary control, and from somatic innervation to supply sensory and motor inputs. **Parasympathetic innervation** Parasympathetic nerves from S 2-4 nerve roots primarily control erectile function by controlling arterial dilation in the corpora cavernosa. **Sympathetic innervation** The sympathetic nerves from T11-L2 control detumescence and contribute to ejaculation and emission by controlling gland secretions and the release of sperm. **Detumescence:** The subsidence of a swelling, especially the return of a swollen organ, such as the penis, to the flaccid state. 2.2.17 SCI AND MALE FERTILITY In men with an SCI, vascular and anatomic functions mediating erection are generally intact, however, nerve damage leads to impaired reflexogenic erections, psychogenic erections, or both. Sperm production and quality can decrease as well due to a variety of factors such as increased temperature due to prolonged sitting, decreased physical activity, and less frequent sperm discharge. The overwhelming majority of men with an SCI will require some type of intervention to father biological children. **Reflexogenic Erections:** An erection which is initiated by direct stimulation of the genital region. **Psychogenic Erections:** Initiated by thoughts and erotic stimuli, independent of direct genital stimulation. In most men with an SCI, the ability to experience erections is preserved more frequently than the ability to experience ejaculation, with around 95% of men with spinal cord injury experiencing ejaculatory problems. The parasympathetic innervation of the male reproductive system is located in the sacral region S2-4. This region is less likely to be damaged in an SCI as compared to the sympathetic innervation which is located in the thoracolumbar region T11-L2 which is a common site of SCI and is responsible for the ejaculatory function in males. 2.2.19 SCI AND FEMALE FERTILITY In women, an SCI will also impair sexual function, but the impact on fertility is less severe than in males, since female sexual function is not as tightly linked to their fertility as it is in males. Recall that clitoral innervation is similar to penile innervation. **Parasympathetic innervation** Parasympathetic nerves from S2-4 nerve roots control clitoral erection as well as relaxation of uterine smooth muscles. **Sympathetic innervation** Sympathetic nerves from T11-L2 control the contraction of the uterus. Additionally, the somatic innervation of the uterus is derived from both T12-L2 and S2-S 4 and provides pain perception. 2.2.20 SCI AND PREGNANCY Many women experience a transient amenorrhea after suffering a traumatic injury to the spine, but regain normal function after a few months. Similar to men, women with an SCI can often experience changes to their sexual response, such as decreased lubrication. However, since sexual function in females is independent from reproductive function, this does not impair their ability to achieve a pregnancy. Many women with an SCI can achieve a pregnancy without requiring medical intervention. However, pregnancy does exacerbate most problems affecting women with spinal cord injury, and thus require careful monitoring throughout pregnancy. Some of the issues they may experience include higher risk of preterm labor, thrombosis or autonomic dysreflexia, a medical emergency characterized by acute uncontrolled hypertension, bradycardia, excessive sweating, and headache. **Amenorrhea:** The absence of menstruation. 2.2.21 WHY IT MATTERS: FERTILITY AND NEURAL CONTROL In 2012, it was estimated there were 44,000 people living with a traumatic SCI in Canada. Sexual function and the ability to have children are important aspects of human life that are significantly impaired in people with an SCI. Understanding the effects of an SCI on the innervation of the reproductive system provides important insights about normal reproductive function, which informs researchers and clinicians on the best strategies to help individuals affected by an SCI. Furthermore, SCIs can also be caused by degenerative diseases such as osteoporosis, arthritis, cancer, multiple sclerosis, among others. Individuals affected by these conditions often suffer non-traumatic spinal cord injuries or nerve degeneration that can impair reproductive function, meaning they can also benefit from these findings obtained while studying the effects of SCIs on fertility. 2.2.22 FERTILITY AND DISEASE In addition to congenital disorders, fertility can be disrupted by communicable (infections) or noncommunicable (chronic) diseases acquired later in life. Sexually transmitted Infections (STIs) have a direct impact on reproductive function. Some of these conditions affect fertility by virtue of their negative impact on sexual activity. However, many STIs can cause permanent damage to the reproductive tract. Chlamydia is the most commonly reported STI in both Canada and the US. It is caused by the bacterium Chlamydia trachomatis. Symptoms are difficult to detect due to being infrequent and seemingly random. It is estimated that more than 50% of infected males and 70% of infected females are asymptomatic and uninformed of their infection status. 2.2.23 CHLAMYDIA AND INFERTILITY Chlamydia is a curable infection and it is usually treated with antibiotics. However, it can be asymptomatic, meaning it is possible to have the infection for a long period of time before experiencing any noticeable symptoms. If left untreated, chlamydia can become a chronic recurring condition, leading to more serious complications and long-term effects. **Effects in Females** In women, it is the leading cause of pelvic inflammatory disease (P I D), a complication of S T Is where infection spreads to the upper reproductive tract. The inflammatory response caused by the presence of a pathogen result in injury and scarring of the affected tissue. Thus, the most common onsequences of Chlamydia include long-term pelvic pain and damage and scarring of the fallopian tubes resulting in tubal factor infertility. **Effects in Males** Post-infection complications are less common in males. However, Chlamydia can cause infections of the urethra and epididymis. More importantly, Chlamydia infection is associated with sperm damage via DNA fragmentation, which has been found to be three times higher than in healthy men without the infection. **Tubal Factor Infertility:** Any kind of obstruction that impedes the descent of any fertilized or unfertilized ovum into the uterus through the fallopian tubes and prevents a normal pregnancy. 2.2.24 FERTILITY AND HUMAN PAPILLOMAVIRUS Human papillomavirus (HPV) is the most common viral infection of the reproductive tract. In Canada, it is estimated that more than 70 percent of sexually active men and women will have a sexually transmitted HPV infection at some point in their lives. Some individuals may be repeatedly infected. HPVs are a group of more than 200 related viruses, 40 of which can easily spread through direct sexual contact, via skin and mucous membranes. Sexually transmitted H P V can remain asymptomatic, or may cause genital warts, which can go away on their own or with treatment. Some types of sexually transmitted HPV can even progress into cancer. However, even non-sexually transmitted HPV types can cause symptoms, primarily non-genital warts. 2.2.25 THE HUMAN PAPILLOMAVIRUS AND CANCER Most high-risk HPV infections occur without any symptoms and go away within 1 to 2 years. However, some HPV infections can persist for years. Persistent infections with high-risk HPV types can lead to cell changes that may progress to cancer if untreated, with high-risk H P V types causing approximately 5% of cancers worldwide. High-risk HPVs cause several types of cancer. - **Cervical cancer:** Nearly all cases of cervical cancer are caused by HPV, with two HPV types (16 and 18), responsible for about 70% of all cases. - **Anal cancer:** About 95% of anal cancers are caused by HPV, most of which are caused by HPV type 16. - **Oropharyngeal cancers:** About 70% of oropharyngeal cancers are caused by HPV type 16. - **Rarer cancers:** HPV causes about 65% of vaginal cancers, 50% of vulvar cancers, and 35% of penile cancers. Most of these are caused by HPV type 16. **Oropharyngeal cancers:** Cancers of the middle part of the throat, including the soft palate, the base of the tongue, and the tonsils. 2.2.26 TREATMENT FOR HUMAN PAPILLOMAVIRUS-INDUCED CANCERS As malignant cancers are highly invasive and can metastasize, they require aggressive interventions. Often these interventions achieve patient survival, but at the expense of specific organ systems. **Surgery** Surgery is often the best approach to excise the cancerous tissue (tumor). Depending on the location of the tumor, surgeries can harm reproductive tissues and cause scarring, which can affect fertility. **Radiation Therapy** This therapy involves the use of high-energy radiation from x-rays, gamma rays, neutrons, protons, and other sources to kill cancerous cells and shrink tumors. As radiation is non-specific, it can equally damage normal cells. Some organs can be protected from the radiation. For instance, the ovaries, can be protected by ovarian shielding or by oophoropexy. **Chemotherapy** Chemotherapy involves the use of drugs to stop the growth of cancerous cells, either by killing the cells or preventing them from dividing. Just as with radiation, chemotherapy is non-specific, meaning it is also toxic to normal cells. Highly toxic drugs, such as those used in chemotherapy, can impair or obliterate the function of gonads. **Hormone Therapy** Hormones used to treat cancer can disrupt the menstrual cycle and the H P G axis, which may then affect fertility. **Metastasize:** The spread of cancer/cancerous cells to other sites in the body by metastasis. **Ovarian shielding:** A procedure in which a protective cover is placed on the outside of the body, over the area of the ovaries and other parts of the female reproductive system to help prevent radiation damage. **Oophoropexy:** A procedure that surgically moves the ovaries away from the radiation area. 2.2.27 HPV PREVENTION There is currently no medical treatment for persistent HPV infections, rather we can only treat the symptoms caused by HPV. However, HPV is preventable. Aside from common methods of prevention of STIs, such as hygiene and condom use, there are available vaccines for HPV. Currently, the Food and Drug Administration (FDA) and Health Canada have approved three vaccines to prevent HPV infection: Gardasil®, Gardasil®9, and Cervarix®. The first has been available since 2006. These vaccines have been shown to provide significant protection against acquiring an HPV infection. However, they are not effective for treating established HPV infections or disease caused by HPV. Traditionally these vaccines have been used in girls/females, but more recently males have started to get vaccinated. 2.2.28 FERTILITY AND CHRONIC DISEASE Chronic conditions often develop later in life, the causes of which are usually not easily defined. Instead, the risk of developing such conditions depends on individual susceptibility factors that are often hereditary. These factors, combined with lifestyle factors, can result in the development of a condition. Some specific chronic conditions that have been strongly associated with decreased fertility in both men and women include hypertension, type II diabetes, and cardiovascular disease. These chronic conditions are often called aging-associated conditions, because they develop over long periods of time due to a combination of factors, and thus tend to emerge in older adults. The mechanisms by which chronic conditions impair reproductive function, and thus fertility, are varied, complex and often not well understood. In this section, we will focus on Type 2 Diabetes as an example. 2.2.29 DIABETES AND FERTILITY Type 2 Diabetes is a chronic disease caused by the body\'s inability to respond properly to the action of insulin produced by the pancreas, known as insulin resistance. Both male and female fertility is impacted by abnormal insulin activity. **Effects in Females** In women, type 2 diabetes is associated to alterations in the length of the menstrual cycle, and the age of onset of menopause, although the mechanisms are not well understood. Insulin, through its own receptor, has been demonstrated to have a direct effect on steroidogenesis in the ovaries. Under normal physiological conditions, insulin acts as a co-gonadotropin in theca cells. However, hyperinsulinemia can potentiate gonadotropin-stimulated ovarian androgen synthesis. Insulin resistance is also observed in polycystic ovarian syndrome (PCOS), a common endocrinology disorder that is estimated to affect between 5% and 10% of reproductive age women, and this pathology is often characterized by some aberrations in the secretion of gonadotropins and, in particular, with high levels of LH (luteinizing hormone). **Effects in Males** Male fertility is known to be seriously impacted by diabetes. Like in females, the exact mechanisms are still unknown. Diabetes in men is associated with erectile dysfunction and ejaculatory dysfunction. This is thought to be caused by diabetes-induced autonomic neuropathy and vascular disease, which is a major cause of erectile dysfunction. Diabetic men have a dramatically higher percentage of sperm with nuclear and mitochondrial DNA fragmentation, with the damage being oxidative in nature. Sperm D N A damage is known to be associated with the decreased embryo quality, the lower implantation rates, and, possibly, the early onset of some childhood diseases. **Insulin resistance:** This is a disorder characterized by an impaired metabolic response to either exogenous or endogenous insulin, with effects on carbohydrate, lipid and protein metabolism. It is believed to be induced by dietary habits and obesity, although it can develop in the absence of obesity. **Insulin:** A hormone produced by the pancreas that promotes the absorption of blood sugar into cells. **Hyperinsulinemia:** A condition in which there are excess levels of insulin circulating in the blood relative to the level of glucose **Autonomic neuropathy:** a group of symptoms that occur when there is damage to the nerves that manage every day body functions. 2.2.30 FERTILITY AND LIFESTYLE FACTORS Lifestyle factors include any individual factors that are modifiable and can affect health, so they are components of an individual\'s medical history. For example, one of the most studied lifestyle factors is nutrition. The effect of nutrition on overall health is a well established but complex and poorly understood. Therefore, there have been numerous studies examining the impact of nutrition on fertility. The human body needs macronutrients (carbohydrates, proteins and lipids) to produce energy, while micronutrients (vitamins and minerals) are required only in small quantities, but are essential for normal physiologic functions. The diagram shows several lifestyle factors that can impact fertility. Each of this is an active area of research. In this section we will specifically focus on nutrition. 2.2.30.1 MALNUTRITION: UNDERNUTRITION Malnutrition refers to all deviations from adequate and optimal nutritional status, including undernutrition and overnutrition. In states of undernutrition, the body lacks the nutrients it requires to produce energy or to maintain its cellular processes, and pathology ensues. When energy is scarce, the mechanisms that distribute energy throughout the body favour the processes that ensure survival over processes that promote growth and reproduction. Conditions of energy deficit, such as eating disorders, malnutrition and extreme physical activity, are associated with decreased fecundity and infertility, mainly via the disruption of hormones of the HPG axis. Food deprivation has been shown to disrupt the G n R H pulse. Inhibition of GnRH secretion leads to a cascade of inhibitory effects, including decreased gonadotropin secretion, inhibited synthesis of gonadal steroids, and impaired gametogenesis. 2.2.30.2 MALNUTRITION: OVERNUTRITION However, overnutrition is considered a form of malnutrition that has become more common in the last few decades, particularly in developed countries. In this case, nutrient intake is oversupplied such that the body\'s metabolic capacity to assimilate them is surpassed. Overnutrition can induce maladaptive responses that result in pathology, such as hyperlipidemia (excess circulating levels of fat), hyperglycemia (high blood sugar), hyperinsulinemia (high insulin levels), among others. As you learned earlier in this section, hyperinsulinemia can potentiate gonadotropin-stimulated ovarian androgen synthesis, increasing androgen secretion, impacting fertility. Overnutrition can also have a negative impact on energy homeostasis by forcing the body to compensate for excess nutritional intake; for example, abnormal glucose homeostasis, which will be covered on the next slide. 2.2.30.3 THE IMPACT OF GLUCOSE ON FERTILITY Abnormal glucose homeostasis has both an impact on male and female reproductive abilities. **Females** In females, insulin resistance (IR) is strongly associated with polycystic ovarian syndrome (PCOS), a hormonal reproductive disorder characterized by abnormal gonadotropin secretion and ovarian androgen production. Insulin resistance is considered to be a precursor to the development of type II diabetes. **Males** In males, abnormal glucose homeostasis is believed to negatively affect sperm cell metabolism. Sperm cells need energy to acquire and maintain motion competence after epididymal maturation. Sperm mainly utilize sugars as an energy fuel and require membrane proteins to act as glucose transporters (GLUTs) to transport glucose across the cell membrane. Various GLUTs in sperms endow them the flexibility to adapt to changes in the environment, metabolic requirements, etc. However, an abnormal environment like diabetes can cause dysfunction in nutrient transport, thus leading to the decreased fertility and adverse fetal outcomes. Other commonly studied lifestyle factors include: physical activity, alcohol intake, smoking habit, drug use, and even medication use, all of which are important components of an individual\'s medical history and have an impact on fertility. SECTION 03: CLINICAL MANAGEMENT OF FERTILITY After infertility is diagnosed, medical interventions are employed to overcome infertility. These interventions are collectively known as assisted reproductive technologies (ART). The most commonly used ARTs include intrauterine insemination (IUI), in vitro fertilization (IVF), third party-assisted ART, which you learn about in greater detail in this section. 3.2 ASSISTED REPRODUCTIVE TECHNOLOGIES (ART) The process of treating subfertility infertility encompasses a variety of methods collectively known as assisted reproductive technologies. Depending on the cause of infertility, one or several methods may be used with the goal of achieving a pregnancy, usually going from the most minimally invasive to the more involved interventions. In these procedures, sexual intercourse is bypassed, and fertilization occurs in a controlled environment. **Intrauterine Insemination (IUI)** In this procedure, insemination is achieved by using a catheter to deposit sperm directly into the uterine cavity as close to the fallopian tube as possible. **In Vitro fertilization (IVF)** A procedure where eggs and sperm are incubated in a laboratory to produce a viable embryo. The embryo is then transferred to the woman's uterus. **Third Party-Assisted ART** Any procedure where someone other than the parents, aids in reproduction. This includes procedures such as: surrogacy, egg/sperm donation. 3.3 VIDEO: INTRAUTERINE INSEMINATION (IUI) Watch the video for an overview of the procedure of intrauterine insemination. In this procedure, insemination is achieved by using a catheter to deposit sperm directly into the uterine cavity, as close to the fallopian tube as possible. This procedure is most commonly used to treat male factor infertility issues (low sperm count, low motility, erectile dysfunction), or certain female issues (presence of anti-sperm antibodies in cervical mucus, dyspareunia). It can also be used to help same-sex couples achieve pregnancy with either a donor sperm or a surrogate. We will expand on third party assisted reproductive technologies in upcoming slides. **Dyspareunia:** Difficult or painful sexual intercourse. 3.4 INTRAUTERINE INSEMINATION (IUI) PROCESS IUI may or may be combined with controlled ovarian hyperstimulation (COH), where a hormone injection is used to promote maturation of additional follicles, to increase the odds of a successful pregnancy. Ultrasound and blood tests are used to monitor follicle maturation and determine which ovary is producing the mature follicle. A trigger injection of HCG is used to control the timing of ovulation and insemination, to ensure the sperm is deposited in the fallopian tube before ovulation. Before insemination, a sperm wash is performed to remove sperm with abnormal morphology and retain the normal sperm. If UIU is not successful the first time, it is recommended to be repeated several times before attempting more invasive procedures. **Controlled Ovarian Hyperstimulation (COH):** A technique used in assisted reproduction involving the use of ovarian stimulatory drugs to cause ovulation by multiple ovarian follicles. 3.5 VIDEO: IN VITRO FERTILIZATION (IVF) IVF is a procedure in which eggs and sperm are incubated in a laboratory to produce a viable embryo. The embryo is then transferred to the woman's uterus. IVF can fail for some women, and one of the major reason for failure is the inadequate quality of the embryo. Age of the eggs, diseases and lifestyle factors are some other possible factors that could be responsible for IVF failure. 3.6 STEPS OF IN VITRO FERTILIZATION In vitro fertilization typically involves 5 main steps. 3.6.1 1. OVARIAN STIMULATION Also known as superovulation, injected hormones are used to promote the maturation of more than one follicle. This hyperstimulation increases the success rate of pregnancy. 3.6.2 2. EGG RETRIEVAL Eggs are collected from the ovaries by inserting a hollow needle through the vaginal wall to access the ovary. An ultrasound is used to guide the needle through the process. 3.6.3 3. SPERM RETRIEVAL The male provides a semen sample that will be used in the laboratory to combine with the egg. The sperm are centrifuged to concentrate it and reduce the volume of semen. 3.6.4 4. FERTILIZATION The concentrated semen is placed in a petri dish with the egg and incubated overnight to fertilize. If the sperm are not able to fertilize the egg on their own, fertilization is then performed via intracytoplasmic sperm injection (ICSI). 3.6.5 5. EMBRYO TRANSFER IVF embryos are transferred to the uterus 1-6 days after fertilization, by using a long tube to inject it directly into the uterus. 3.7 THIRD PARTY-ASSISTED ART These procedures are usually selected when other approaches fail or are not applicable. There are several forms available. **Sperm Donation** In cases of male sterility or in the case of a genetic disease, donated sperm can be used to perform IUI or IVF. **Embryo Donation** Also known as embryo adoption, is used in cases when both partners are infertile or when all other ART approaches have failed. Embryo donation allows a recipient mother to experience pregnancy and give birth to the adoptive child. IVF procedures often result in additional viable embryos that can be donated by the parents. These embryos can be frozen and made available for adoption via an embryo donation agency. **Gestational Surrogacy** Similar to traditional surrogacy, except that the carrier is implanted with an embryo that is not biologically related to her. This can be used when the woman does produce healthy eggs but is unable to carry the pregnancy to term. **Egg Donation** In female infertility such as ovarian insufficiency, genetic disease, and other issues with egg production, donated eggs can be used to be fertilized by the woman's partner. An egg donor will undergo ovarian hyperstimulation and egg retrieval, and the donated eggs will be fertilized with IVF. The resulting embryo can then be placed into the woman's uterus, after hormonal treatments to make the uterus receptive. **Traditional Surrogacy** In cases where a woman is unable to carry a pregnancy to term, a couple may choose to select a surrogate. A surrogate is inseminated with sperm from the male partner, which will produce a child that is related to the male partner and the surrogate. 3.8 COMPARING ASSISTED-REPRODUCTIVE TECHNOLOGIES **Intrauterine Insemination (IUI)** - Natural conception is failing for unknown reasons - Male infertility factors - Difficulty with sexual performance - Cervical problems **In Vitro Fertilization (IVF)** - I U I has failed multiple times - Fallopian tube abnormalities - Chronic reproductive disease - Low sperm count in male **Third Party-assisted ART** Pregnancy is not achieved using IUI or IVF