Having babies is a right and wish of all the couples after marriage, but an intact hormonal system, psychological stability, and emotional composure are the merits for achieving due to maturation of the sperm and ovum leading to the fertilization followed by the birth of a healthy being. Fertility refers to the ability to conceive and bear offsprings, while fecundity expresses the prospect of women to reproduce on a monthly basis. The incompetence of a couple to conceive after more than 12 months of unprotected intercourse is called “infertility.” According to the World Health Organization, “infertility is the inability to conceive a child.” Inability of a woman to become pregnant after 1 year of regular intercourse for what so ever the cause may be labels the couple as infertile.
Infertility is consistent with all cultures and societies and affects an estimated 10%–15% of couples of reproductive age worldwide. Every one in six couples is affected by this debarment. Infertility is prevalent in all societies of the world, including 50% of West African societies, 12% of Western European families, and 23% of couples in Pakistan. This universal burden is growing at a tremendous rate with topographical variations and affecting the quality of life of not only the married couples but also families at large. It is undoubtedly a key threat to a married female and demands financial stability for its investigation and choice of treatment plans eventually.
Infertility is taken as a problem in every culture and society and is considered to affect approximately 10%–15% of couples of reproductive ages. Lately, the graph of treatment-seeking couples for infertility has gone high due to many factors including delayed marriages, belated childbearing in women, and knowledge of the development of successful new techniques for infertility treatment.
Infertility can be classified as “primary infertility,” a condition where the female is deprived of conceiving at all or has been unable to carry on pregnancy fruitfully to a live birth, and “secondary infertility,” where the female is incapable of conceiving a new pregnancy for 1 year following a previous pregnancy. Primary infertility contributes 5% of the 23% infertile couples while secondary type of infertility is approximately three times more.
According to WHO-DHS Comparative Report, 2004, approximately 186 million women of the developing countries (excluding China) are suffering from any type of infertility. This number represents that in every four ever-married women, more than one woman is subfertile during their reproductive age. The prevalence of infertility in Pakistan is approximately 23%, where primary infertility contributes to 3.5%–3.9% and secondary infertility is 18.0%–18.4%.
Determinants of male subfertility
Men and women are equally (40%) responsible for infertility while the remaining 20% couples have no identified cause for conception (unexplained infertility). Apart from physiological variations, three types of factors can act by themselves or interact in complex pathways, which are environmental, genetic, and physiological. The causes are summarized in Fig. 5.1 .
Known etiology of male factor subfertility is around 10% and repeated specimen analysis of semen can reduce this rate to 2%. The normal values of semen characteristics are given in the previous chapter.
Male infertility contributes to 40% of the total cases of subfertility. Abnormal semen characteristics have no reason (idiopathic) in around 26% of infertile men. Oligoasthenoteratozoospermia is characterized by dysfunctional spermatozoa, whereby some percentage of sperms is incapable of fertilization. Antisperm antibodies are a probable cause of this condition.
Hypothalamic pituitary failure may lead to azoospermia. Its two types are nonobstructive azoospermia causing primary testicular failure and obstructive azoospermia causing the obstruction of the genital tract.
Less than 1% of the infertile men problems are due to hypothalamic or pituitary dysfunctions. In this case, luteinizing hormone and follicular-stimulating hormone are less than normal, which affects the normal spermatogenesis and testosterone production and secretion.
Causes of female subfertility
In general, the causes or factors of female infertility can be classified based on whether they are acquired or genetic, or strictly on the basis of location. Causes of infertility in the Pakistani population can broadly be categorized into male factors (23%), female (44%) or unexplained infertility (28%), and coital factors (5%).
A number of dietary, infectious, environmental, endocrine as well as hormonal imbalances can be the contributing factors. Hence, female infertility turns out to be a pressing global burden, especially in South Asian countries. It is a well-known fact that the scale of infertility spreads from the reproductive disorders leading to detrimental psychological as well as social implications ( Fig. 5.2 ).
The known causes of infertility are mostly related to defects in fallopian tubes, uterus, or hormonal balance. The increase in age at the time of marriage due to the attainment of higher education is another contributing factor. Increased age (> 35 years) affects the efficiency of ovaries and has been documented to be reciprocal with reproductive capacity. Additionally, females being work-oriented and pursuing professional growth tend to spend hours at a job, and later, being tired has also decreased the frequency of sexual intercourse and increased the chromosomal abnormalities and rate of abortions.
Apart from physiological aspects, the occupation of the couple is another point of concern. Long working hours or shift duties may affect the frequency and correct timings of sexual intercourse. Exposure to radiations, harmful substances, and heat is likely to reduce sperm parameters in males. Living in a joint family system with the burden of household chores makes workingwomen too tired to be available to male partners. Monitoring the body basal temperature or maintaining a monthly chart of the menstrual cycle could be helpful in achieving conception by coinciding with ovulation.
The consumption of alcohol has not been effectively found to be associated with female infertility, but excessive alcohol intake has reversible detrimental effects on sperm quality. However, smoking has a strong association with delayed conception, reducing infertility in females and with derangement of sperm parameters in males. There is no consistent evidence to demonstrate an association between caffeinated drinks and fertility difficulties.
Obesity stands as a well-known independent risk factor for not only cardiovascular diseases and diabetes mellitus but also reproductive malfunction in both males and females and has been associated with lower success rates following assisted reproduction. Integral differences of oocytes in these obese patients increase with the duration of stimulation, decrease number of oocytes, and affect oocyte maturity, implantation, and clinical pregnancy rates. Obesity impacts females starting from menstrual irregularities to delayed conception and spontaneous abortions in females; obesity has a negative association with erectile function and normal amount motile sperms.
Endometriosis is a term given to a condition where the endometrial tissue is found outside the uterine cavity. It accounts for 5% of female infertility and is characterized by peritoneal lesions, adhesions, and cysts. Mild endometriosis is equivalent to unexplained infertility in females.
Uterine abnormalities include uterine or cervical polyps, submucosal leiomyomas, and adhesions within the reproductive tract. Bicornuate uterus is also a contributor to female infertility. The reason for this association has to be elucidated.
Gonorrhea, tuberculosis, and chlamydiasis are the most common causes of infection of the female reproductive tract. During infection, the tubal lining is damaged, which later causes adhesions that interfere with the normal ovum transport to the appropriate site of fertilization and implantation. These sequelae may result in ectopic pregnancy, abscesses, pelvic inflammatory diseases, and hydrosalpinx. Infections from chlamydia trachomatis range from 11% to 13% in the young population. It stands as a major cause of pelvic inflammatory disease resulting in abdominal pain, ectopic pregnancies, or infertility due to tubal incompetence. Routine uterine investigations for infertility, including cervical hysterosalpingography, might extend or reactivate the infection. Cervical cancers have also been reported as the cause of delayed fertility.
Genetic trait of subfertility
Chromosomal aberrations and gene variation are common causes of infertility. Obesity being a part of PCOs suggests that genes responsible for causing PCOs are employed in reproductive hormone regulation, steroid biosynthesis, and insulin sensitization. Calcium dependency for egg activation, oocyte maturation, follicular growth, and embryo development involves the vitamin D receptor genetic mutations to be associated with PCOs. Apart from genes directly involved in reproductive hormones, mitochondrial genes have also been associated with female infertility.
Unexplained subfertility is a term used when a couple is incapable of conceiving with no detachable cause. It includes 40% of the infertile females and about 8%–28% of the infertile couples, worldwide.
A lot of research is focused on the evaluation of oxidative stress as a cause of infertility in females. Evidence proves the presence of altered redox environment in the sperms and the seminal fluid; however, the evaluation of oxidative disturbances in the granulosa cells and the follicular fluid needs to be investigated in depth. Occupation, long working hours, and presence of emotional stress on the infertile females play a major role in developing this condition, which becomes one more factor for unsuccessful attempts to assisted reproductive techniques (ART). Details of ART are discussed in Chapter 6 .
Current methods employed for investigating subfertility and challenges faced in clinical practice
Assessment of male factor infertility
As per the guideline development group, the sperm analysis criteria set by the WHO for the detection of male factor infertility are not specific but sensitive; thus, semen specimen should be retested two to three times to reduce false-positive cases.
Hypothalamic pituitary failure (nonobstructive) and patency of the genital tract (nonobstructive) should be examined in the case of azoospermia.
Cervical mucus postcoital testing (PCT): As per the evidence, there is no effect of the PCT on the treatment strategies.
Assessment of ovarian disorders
Evaluating ovarian reserves
The fertility of a woman is directly proportional to its ovarian reserve. With an increase in age, the reserve declines and thus decreases the probability of becoming pregnant. Apart from age, the hormonal levels are very important determinants of the ovarian reserve. Antral follicle count (AFC), anti-Mullerian hormone (AMH), follicle stimulating hormone (FSH), and clomifene citrate challenge are recognized to fulfill the accuracy criteria for detecting the ovarian reserve. However, after analysis, these tests are unable to predict live birth accurately. Live birth is the most important and desirable outcome from all tests and treatments thus demands determination of accurate cutoffs for its prediction.
Regularity of menstrual cycle
The cycle ranging from 26 to 39 days is considered as a normal regulation of menstrual cycle. It is characterized by the luteinizing hormone (LH) surge, which can be detected by monitoring basal body temperature. Urinary LH kits are also helpful in identifying forthcoming ovulation. Mid-luteal progesterone levels around 21st day are also indicative of ovulation but are very nonspecific in females with irregular cycles.
Thyroid function test
Screening infertile females for thyroid function has been a routine, as hypothyroidism is known for causing disturbed menstrual and anovulatory cycles.
Tubal and uterine disorders
Hysterosalpingography vs laparoscopy with dye
Both invasive procedures are widely used to detect the patency of the ovarian tubes, where they identify tubal blockade as a cause of infertility they show no reliability for positive pregnancy outcomes.
Laparoscopy stands as a gold standard for uterine pathologies; however, HSG records the patency.
This transvaginal microendoscopy approach is well recognized for the detection of the entire fallopian tube patency. Furthermore, studies show that 24% of females conceived naturally after this procedure.
Tubal flushing showed a significant increase in pregnancy rate when performed with oil-soluble contrast. However, further studies to assess the effect of water-soluble media on the pregnancy rate and outcome are warranted. Anaphylaxis and lipogranuloma have been reported to occur as a consequence of this tubal patency testing.
Ultrasound of pelvis
Still standing as the first-most line of investigation to rule out pelvic pathologies, ultrasound pelvis provides great accuracy and reliability.
Various techniques are used to reduce the transmission of sexually transmitted diseases depending on the virus under the suspect. An approach like sperm washing is used to prevent hepatitis C while hepatitis B can be prevented via vaccines. In vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI)play a great role in prevention from human immunodeficiency virus (HIV) as this technique provides a washed sperm preparation. However, sperm washing does not guarantee the complete elimination of the virus.
Less invasive and more cost-effective treatment ways include antiviral therapy for couples where one partner is HIV-positive.
Role of Chinese herbal medicine for treating PCOS
PCOS is a combination of obesity, insulin resistance, and hyperlipidemia; thus, a true picture of metabolic syndrome patients. Chinese herbal medicine (CHM) is widely used for various metabolic dysfunctions involving kidneys, heart, and liver. It is also used in treating menstrual disorders, hirsutism, and improving pregnancy rate in PCOS patients.
Routinely CHM is considered as a safe regimen provided prescribed appropriately by qualified practitioners. There are serious concerns about unfavorable incidents, including allergic reactions and kidney involvement like Chinese herbal nephropathy (CHN) . Utilization of this type of therapy needs a detailed research before labeling it reliable.
Evaluation of genetic problems
Before finalizing the treatment of subfertility in both males and females, genetic defects should be considered and discussed in detail with the couple in order to be explicit about the outcomes. Karyotyping should become a routine investigation, especially in infertile males with deformed sperms and nonobstructive azoospermia. Microdeletion of Y chromosome is not very common and thus not regarded as a part of routine investigation.
ICSI and IVF are popular choices of infertility treatment. ICSI has a better fertilization rate; however, pregnancy rate is observed to be better after IVF.