Infertility is a highly prevalent topic that is continuously researched because of the powerful desire to have children worldwide yet numerous problems associated with conceiving one. World Health Organization (WHO) refers to it as a “disease of the reproductive system”. Problems with fertility are seen to be as common with men as it is with women. As more people are postponing their first pregnancy, there is a higher likelihood of limitations in fertility. Genetic abnormalities, environmental agents and behavioral habits greatly affect the health of one’s reproductive system and interfere with reproduction. This article is intended to discuss the causes as well as various treatments and alternatives for infertility.
What is considered infertile? It does not always mean you are unable to ever have a child. According to HYPERLINK ‘http://obgyn.ucla.edu/default.cfm’UCLA Obstetrics and Gynecology, it is defined as the inability to conceive within 12 months (1). Some doctors believe if one does not get pregnant within a year of regular unprotected sex, they are most likely to be infertile. This also includes women who are unable to stay pregnant or maintain a desired pregnancy. Even more petrifying, pregnant women over 35 are deemed infertile if they are not pregnant within 6 months of having unprotected sex. This places a significant number of couples in this category, making infertility a major healthcare problem. About 10 percent of women (6.1 million) in the United States ages 15-44 have difficulty getting pregnant or staying pregnant, according to the Centers for Disease Control and Prevention (2)
Understanding the processes that must occur in order to get pregnant is crucial in defining what normal fertility really is. It requires the release of a healthy egg from a woman’s ovaries (ovulation), passage of the egg through the fallopian tube to the uterus, fusing of a viable sperm with the egg (fertilization) and the fertilized egg attaching to the lining of the uterus (implantation). Problems with any of these steps can result in infertility (3) and may arise in various ways ranging from genetic abnormalities to environmental factors. Every step of the journey towards pregnancy is characterized by interactions among the physical and social environment, the biological background and behavior of individuals, and the health care system (1). However, as research in this field continues to expand, there are higher success rates with detecting, evaluating and resolving infertility issues which can be as simple as just creating awareness regarding lifestyle habits and such.
Determining if someone is fertile or not involves series of physical tests and examinations as well as medical and sexual histories of both partners known as infertility tests. The information necessary for these tests include knowing of any existent pain during intercourse, previous sexually transmitted infections and/or abnormal pap smears, any prior surgeries, family history of medical problems and so on. Another important tool for evaluating fertility is conducting an ultrasound to detect abnormalities like ovarian cysts and deduce how many eggs are available for potential fertility. Blood tests may also be used to determine the levels of hormones related to ovarian health such as follicle stimulating hormone, estradiol, prolactin and thyroid stimulating hormone. If a woman is ovulating, a hysterosalpingogram (an x-ray of fallopian tubes and the uterus) would be used to discover any tubal abnormalities that prevents movement of eggs through the fallopian tubes. (1)
Although the focus of research has primarily been on women, the inability to have children is just as common among men (fig. 1). A semen analysis is conducted on men to evaluate sperm volume (should be 1.5-2ml minimum), sperm concentration (at least 20 million sperm per 1 ml of semen), sperm motility and shape or morphology of the head, midpiece and tail. (1)
Causes of Infertility in Women
Absence of ovulation (anovulation) or disruption in ovarian function as a whole is a very common cause of infertility. A normal menstrual cycle lasts 28 days long on average, and ovulation occurs about 10-16 days before menstrual flow (or period). The luteinizing hormone (LH) increases 24-48 hours prior and triggers the release of an egg. If a woman has infrequent or absent ovulation, there is most likely disruption in the production of hormones released from the gonadotropin releasing hormone in the hypothalamus or the pituitary gland (which releases LH).
Polycystic Ovary Syndrome is the condition that causes women not to ovulate regularly or at all.
Obstruction in fallopian tubes that carry eggs from the ovary to the uterus also play a large role in infertility. This can include benign growths like polyps and fibroids or scarring due to prior surgery. A disease called endometriosis is a contributing factor as well in which tissue normally found in the uterus grows elsewhere (5). Chlamydia or Gonorrhea are sexually transmitted diseases that can be can spread to fallopian tubes (along with womb and uterus as well leading to pelvic inflammatory disease) and can also result in difficulty getting pregnant.
Maternal age is also known to affect fertility. The proportion of first births to women aged 30 years and older has increased more than fourfold since 1975, from 5% to 24% in 2006, according to CDC (10). A woman’s fertility has proven to decline with age because aging decreases; the number of eggs in their ovarian reserve, the proportion of healthy eggs and the likelihood of an egg being genetically normal. The reason for this remains unknown but the consequences are grave especially as female-age related infertility is the most common cause of infertility today. It was not evident before this century when women were conceiving in their teens and early twenties but it becomes more apparent as more women do not think of having their first child till their thirties. A woman is seen as rarely fertile past the age of 45. (1)
Approximately 5-10% of infertile women have complications that go beyond their basic reproductive needs. They may have underlying genetic abnormalities, chromosome aberrations and genetic mutations. (4). Trisomy X is a syndrome known to cause premature ovarian insufficiency (POI). Most women with the syndrome appear normal but others suffer from POI. Some genomic regions associated with female infertility were discovered and it was found that null mutations in genes, SYCE1 and CPEB1 are responsible for ovarian failure in female mice. (8)
Causes of Infertility in Men
Age also plays a role in male fertility although it is much more dramatic and significant in female infertility, male partners over the age of 40 tend to have more trouble conceiving Although, unlike the limited number of eggs available to women at birth, men create 100-200 million fresh sperm each day, age-related fertility decline is still present in males. In study conducted of over 8000 pregnancies, men over the age of 40 were 30% less likely to conceive compared with men under 35. Another demonstrated that in 1,976 women, it took men over 45 five times the average time to pregnancy compared to men 25 years and under. (9). Age-related decline in fertility in men is caused by decreased sperm motility, morphology and volume.
Varicocele is common condition that is approximately two-thirds of office visits and half of surgery services for male infertility in the United States (10). It occurs when the veins in testes are enlarged affecting the overall quality of sperm produced. A man’s sperm quality can also be affected by illness (including infections like epididymitis, inflammation of the testicles, sexually transmitted diseases or cancer/tumors that affect reproductive glands). There are issues with production of sperm/ejaculation such as premature ejaculation, erectile dysfunction or even ‘retrograde ejaculation’ in which the semen enters the bladder during orgasm instead of through the tip of the penis.
Chromosomal defects can cause abnormal development of the male reproductive system and has been detected in about 20% of infertile men. (8). The defects can either be numerical or structural and increasing chromosomal aberrations have been seen to proportionally increase the severity of infertility. Klinefelter syndrome (47,XXY) and 47,XYY syndrome are numerical sex chromosomal abnormalities in males are relatively common with each occurring in approximately 1–2 in 1000 live births. (11). Chromosomal translocations are structural and involve the breaking of two chromosomes with an abnormal repair of the fragments resulting in the translocation of one gene to a different region without loss of genetic material. These are phenotypically normal unless the breakpoint interrupts an important gene which is high risk for infertility.
Lifestyle and Environmental factors
Certain modifiable behaviors and external factors impact the rate of female and male fertility decline. Unlawful use and overdone of steroids, cocaine, alcohol and tobacco can reduce the likelihood of pregnancy as well as the possible effectiveness of fertility treatment. Tobacco use is associated with lower probability of conception in a month in women, and it lowers volume of sperm and changes morphology of sperm in men. According to Dr. Jackie Gutmann, women who smoke add ten years to their reproductive ages, therefore a 30 year old smoker would have the reproductive potential of a 40 year old (12)
Environmental and occupational hazards are suspected to create fertility impairments as a result of prolonged exposure to harmful chemicals/toxins. This can lead to delayed fecal growth, miscarriage and birth defects. Durham Health department’s Health and Wellness resources highlights the common substances pregnant women should avoid which are paints, pesticides, mercury just to name a few.(13)
Being overweight and underweight affect both genders, putting them at higher risk of infertility (erectile dysfunction is more common in obese men). Poor diet lacking in nutrients, stress, current medications and so on are additional common factors. Regarding cancer, the negative effects of specific chemotherapy and radiation treatments include interference with reproduction.
Education is the best tool we possess in reducing the risk of complications that affect fertility. Not only will it empower people to make better choices, understanding how normal reproduction works is beneficial in knowing when it is best to seek help. 7.4 million women, or 11.9% of women, have ever received any infertility services in their lifetime. (2006-2010 National Survey of Family Growth, CDC, 2). Options best for a person or couple depends on the kind or cause of their fertility issue.
Medications can be used to induce ovulation and these can come in either pill or injection forms. A commonly prescribed pill is clomiphene citrate which is taken between the third and seventh day of the menstrual cycle. Clomiphene is an anti-estrogen which binds to estrogen receptors in the hypothalamus leading to an increase in release of gonadotropin releasing hormone (GnRH) and binds to the pituitary gland leading to release of follicles stimulating hormones for egg growth. The injections stimulate the ovaries (gonadotropins) by introducing the FSH and LH directly into the body to act directly on cells and stimulate egg development (e.g Human Chorionic Gonadotropin/HCG)
Assisted Reproductive Technology (ART) has been used in the United States dating back to 1981 (10) to treat help infertility. Data is constantly being collected by the CDC as mandated by the Fertility Clinic Success Rate and Certification Act of 1992 (FCSRCA) (Public Law 102–493 [October 24, 1992], 14) (Fig 2). The results in 2015 were: total of 182,111 ART procedures (range: 135 in Alaska to 23,198 in California) resulting in 59,334 live-birth deliveries (range: 55 in Wyoming to 7,802 in California) and 71,152 infants born (range: 68 in Wyoming to 9,176 in California). Nationally, the number of ART procedures performed per 1 million women of reproductive age (15–44 years), was 2,832. (14).
ART includes common procedures like In Vitro Fertilization (most effective type of ART), intracytoplasmic sperm injection, and may involve use of fertility medication. In Vitro Fertilization is a technique of retrieving male and female gametes (sperm and egg) and letting fertilization occur outside the female body – donor sperm/eggs or previously frozen embryos can be used. Since the first IVF baby was born in England in 1978 and one was delivered in the United States a couple of years after, the use of IVF has grown dramatically. It is a groundbreaking procedure that has allowed many women deemed permanently infertile to give birth to health babies. Transvaginal ovum retrieval is the method used to retrieve eggs by inserting a needle through the back of the vagina (guided via an ultrasound) to collect fluid containing eggs. Embryo transfer is the process of placing the fertilized eggs (or embryos) back into the uterus of the female. Intracytoplasmic sperm injection helps where sperm counts are very low and multiple IVF attempts have failed. A single sperm is injected into the center of an egg, however, this is not as common not only because a large number of sperm needs to be produced with this method but one has to be extremely careful while injecting. (Fig 3)803272328427
The most prevalent complication of ART is multiple pregnancy which typically results from the use of multiple embryos. It is pretty difficult to predict or determine how many eggs would be fertilized which is why more than one is used. Multi-birth infants have much higher risk of infants death, disability, and pre-term delivery. The simplest strategy to check/reduce the chances of multiple pregnancy is by limiting the number of embryos transferred into the woman’s body.
Even more common than ART, Ovarian stimulation by natural conception or intrauterine insemination (IUI) exist in which a sperm is placed inside a woman’s uterus directly to facilitate fertilization. This is done in order to increase the number of sperm that reaches the fallopian tube/egg and consequentially increases the chance of reproduction, however, the sperm used cannot have severe abnormalities. The sperms are washed in solution safe for both sperm and egg and painlessly injected into the uterine cavity for fertilization. Efficacy of this treatment is sadly generally lower than that of ART with pregnancy rates generally below 15%; for a review of trials of ovarian stimulation and IUI (10).