Special Columns

Introduction and Treatment of Infertility

Dr. Long-Jen Chen

Division of clinical toxicology and occupational medicine, Department of internal medicine, Taipei veterans general hospital

I. The definition of infertility

Infertility is “a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse.” (WHO-ICMART glossary). When a woman is unable to ever get pregnant she would be classified as having primary infertility. Secondary infertility, by contrast, defined as unable to bear a child following a previous pregnancy. Regardless of the cause of infertility, a comprehensive evaluation is necessary before appropriate treatment.

II. The cause of infertility

The causes of infertility solely from male and female are 40% and 40% respectively. In the remaining cases, there are abnormality with both the male and female. Therefore, both couples required to be adequate evaluated in the event of infertility. Nevertheless, even under adequate examination, no cause can be identified in 5-10% of infertile couples.

III. The causes, examination and treatment of male infertility

The causes of male infertility can be roughly summarized as the following:

A. Abnormal semen: low sperm count, abnormal shape of sperm or low sperm mobility.

B. Abnormal sperm production: congenital anomalies, chromosomal abnormalities, hormonal abnormalities, infectious diseases, varicocele, chronic diseases, trauma, environmental toxins, testicular tumors, medication, etc.

C. Problems with the delivery of sperm: congenital absence of vas deferens or acquired obstruction of vas deferens.

D. Sexual dysfunction: impotence, premature ejaculation or failure to ejaculate, hypospadias, etc.

The first and the most important examination for male infertility is semen analysis, including sperm concentration, sperm total motility and sperm morphology. Genetic or chromosome testing could be done to determine whether there's a genetic defect causing infertility (eg, a balanced transposition, a mosaic chromosomal abnormality).

If there is an issue with the male, it is necessary to seeing the urologist and arrange further examination including history taking, physical examination, ultrasonic examination, blood test, further analysis of semen, etc. to determine the cause of infertility and receive appropriate treatment and follow up. In addition, normal sperm could be obtained by sperm retrieval for treatment of male infertility.

IV. The causes of female infertility

The causes of female infertility can be roughly summarized as the following:

A. abnormal ovulation, hormonal imbalance, ovarian early failure ... and so on.

B. abnormal secretion of cervical mucus, so that sperm can not smoothly enter the uterine cavity.

C. the structure of the uterine cavity is abnormal, the endometrium is too thin or sticky, or abnormal function.

D. The fallopian tube is sticky, distorted, or blocked due to inflammation or infection.

E. other factors in the abdominal cavity (such as: endometriosis, pelvic adhesion, ovarian adhesion, etc.).

V Examinations for infertility in female

1、Basal body temperature charting

The cyclic change in basal body temperature provides information on the hormonal surge required for ovulation and also the length of luteal phase which can be monitored by the basal body temperature chart. The periodic change of basal body temperature including the low and high temperature period. The follicular phase of menstrual cycle start from the end of period and persist before ovulation. During this period, estrogen dominate the cycle corresponding the proliferative phase of endometrium and a low temperature period. Following ovulation, the menstrual cycle enters luteal phase with the surge of progesterone preparing the implementation environment of endometrium and turning into high temperature period. This high progesterone-dominated phase and high temperature period will last for 12-16 days. Under the circumstance of no embryo implementation, the endometrial shedding and bleeding occurs followed by the decrease in basal body temperature. For women with insufficient progesterone support, the high temperature period will within 12 days and the the variation in progesterone level will increase. Under such a circumstance, the embryo may fail to implement event with success fertilization.

2、Pelvic examination and Chlamydia DNA examination

Pelvic examination is crucial for the evaluation of female reproductive system including external genitalia, vagina, and cervix and anomaly in uterus and adnexa such as adhesion and tumour. Among the infection of female reproduction system, Chlamydia is the most common pathogen. The disease spectrum of Chlamydia infection in female reproductive system including vaginitis, cervicitis, pelvic inflammatory disease, salpingitis, hydrosalpinx, adhesion, obstruction, chronic pain, and infertility. The persist Chlamydial infection of female reproductive symptom will results in infertility and hence calls for aggressive treatment. Due to the sexual transmission route, both of the coupe require treatment once the infection in female is identified.

3、Transvaginal Sonography (TVS）：

Abnormal anatomy of the reproductive organs is also an etiology that must be checked and excluded for female infertility. Transvaginal ultrasonography is able to detect diseases such as uterine myoma, endometrial polyps, and uterine or ovarian tumors. Important information such as endometrial conditions and follicular growth can also be tracked.

4、Anti-sperm Antibody Exam：

Anti-sperm antibodies may occur in both men and women. Once they occur, they may slow down the activity of sperm or cause sperm to aggregate, which in turn affects fertilization. Men may suffer from damage to the blood-testis barrier due to testicular trauma, vasectomy, epididymal surgery, or infection, which in turn produces antibodies against sperm. The cause of female anti-sperm antibodies is unknown.

In terms of treatment, there are different treatment methods depending on the amount of anti-sperm antibody. (1) The amount of anti-sperm antibody > 30%. It is recommended to try intrauterine injection (IUI) first. If it fails many times, it is then recommended to change the in vitro fertilization (IVF); (2) the amount of anti-sperm antibody > 50 %, use IVF treatment directly; (3) the amount of anti-sperm antibody > 80%, adapt in vitro fertilization with intracytoplasmic sperm injection (IVF-ICSI).

5、Hysterosalpingography, (HSG)：

HSG is a common method to check whether the shape of the uterine cavity is normal and whether bilateral fallopian tubes are patent. During an HSG, contract media was first injected into the uterine cavity. Then under X-ray photography, lesions such as congenital uterine malformation, uterine cavity adhesion, uterine tumor, fallopian tube obstruction or fluid accumulation could be detected. In addition, if bilateral fallopian tubes are slightly obstructed, it is possible that under this examination, the pressure generated by injecting contrast media into the uterine cavity could reopen the obstructed tubes. The limitation of this exam is that it can only discover structural abnormalities, and is not used for functional interpretations. Therefore, even if the fallopian tube is found to be patent, the ovum may still not be able to enter the fallopian tube properly due to previous infection, inflammation, or fallopian cilia damage.

6、Hormonal study：

(1) Anti-Müllerian hormone (AMH): a glycoprotein whose concentration does not change with the menstrual cycle. In the female body, it does not manifest at all during the embryonic period. A small amount of AMH is secreted from follicular cells since birth, and the secretion increased to its highest at the time of adolescence. This hormone regulates follicle maturation and ovulation, and can be used to predict the female ovarian reserve. The AMH value is directly proportional to the ovarian follicle reserve.

(2) Follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), progesterone (P4), and testosterone: change with menstrual cycle. In general, the first screening is performed on the third day of menstruation to determine whether the ovarian function is normal.

(3) Thyroid stimulating hormone (TSH), prolactin: abnormal thyroid function or excessive prolactin may lead to abnormal ovulation in women. The above examination can screen such abnormalities. More importantly, the cause of such abnormalities should be identified and treated.

(4) Cortisol, 17-hydroxyprogesterone (17-OHP): 17-OHP is a precursor of cortisol. A 21-hydroxylase deficiency in women impairs the metabolic pathway from 17-OHP to cortisol, causing congenital adrenal hyperplasia (CAH), or female hirsutism and infertility.

(5) Blood sugar, insulin, and glycated hemoglobin (HbA1c): polycystic ovary and other ovulation abnormalities, often accompanied by high insulin resistance in women, resulting in high blood sugar, insulin, and glycated hemoglobin levels.

7、Endoscopic examination

Hysteroscopic examination is an examination by placing endoscopy into uterus so that doctor can exam the pathologic lesion or abnormality by direct observation through the endoscopy. Indications of hysteroscopic examination are intrauterine adhesion, endometrial polyps, and intrauterine tumor compression, etc. It is not only for diagnosis but also be used therapeutic purpose to remove endometrial polyps, submucous myoma or adhesion at the same time.

Laparoscopic examination is an examination by placing endoscopy into pelvic cavity so that to directly see the structure or the abnormal lesion of uterine, ovary, and fallopian tube and other organs in the pelvic cavity, such as endometriosis, uterine myoma, uterine malformation, adhesion of uterine or fallopian tube, fallopian tube torsion, fallopian edema and any causes that interferes the ovum pass into uterine. During the examination, chromopertubation (instillation of dye through the fallopian tubes) can be performed to assess tubal patency by seeing dye from cervix to fimbria.

8、Examinations of chromosomes and other genetic abnormalities

Chromosomes or other genetic abnormalities, such as chromosome translocation, Chromosome Mosaicism or other abnormalities, can be diagnosed by a blood sampling. Other specific genetic abnormalities can also be found by genetic testing or mitochondria testing.

If the above genetic abnormalities existed, in vitro fertilization (IVF) can be considered. After in vitro fertilization, doctor exams the embryo (5^th day after fertilization, Blastula stage) by performing preimplantation genetic screening (PGS) or preimplantation genetic diagnosis (PGD) to exclude the embryo with significant chromosome abnormality, which will lead to serious or fatal genetic disease, and chooses the normal embryo to perform embryo implantation.

VI、Treatments of infertility

The treatments of infertility are subjected to the cause of infertility. Common assisted reproductive technology (ART) is introduced as following:

1. Oral ovulation stimulator

Oral ovulation stimulator is the simplest treatment for infertility by stimulating the follicular maturation and ovulation. It uses with basal body temperature measurement and ovulation test to predict the ovulatory period and increases the chance to fertility.

This treatment is indicated for the wife with only abnormal ovulation.

2. Intrauterine injection (IUI)

Intrauterine injection is indicated for those whose husband has normal sperm test and wife has at least one side patent fallopian tube.

The procedure is first to stimulate the follicular cell by injection of stimulation drug. Once the condition of the follicular cell matures (size of 16-18 mm) and endometrial thickness is over 8mm, the ovulation stimulator is injected. Fresh sperm of the husband is collected and then appropriately prepared to inject into wife’s uterine. After that, waiting for ovary fertilizing and implanting into uterine cavity.

General speaking, the average successful rate is around 20%.

3. In vitro fertilization (IVF) treatment

The IVF treatment is based on the injection of drugs to stimulate follicular development. After the follicles are mature (about 16-18 mm in size), the injection of human chorionic gonadotropin (HCG) is used for ovulation and transvaginal oocyte retrieval (TVOR) is arranged. Semen is collected in the same day. After the semen is collected and purified, it is fertilized with the ovum in vitro. The fertilized embryo is cultured in vitro for 3 days (eight-cell phase) to 5 days (blastocyst phase). If the wife's endometrial thickness is at least 8 mm and the hormonal value reaches standard value, embryo transfer (ET) can be performed on the 3rd to 5th day, which is called fresh embryo transfer. If the wife has insufficient endometrial thickness, hormonal values do not meet standard value, or have other considerations, the embryos will be frozen and will be implanted in the future. This is called frozen embryo transfer. At present, the embryo freezing technology has matured, and the pregnancy rate of fresh embryo transfer and frozen embryo transfer is similar.

The average pregnancy rate for IVF treatment is around 50-60%. If a woman fails to pregnant many times, or more than three times the artificial insemination fails, a woman is older than 34 years and two times the artificial inseminations fails, a woman is older than 38 years and an artificial insemination fails, or an older patient, it is recommended to receive IVF to increase pregnancy rates. Older women have poor ovarian function, low follicular stock and poor response to drug stimulation. It is recommended to skip the artificial insemination and receive the IVF treatment. In addition, the husband has azoospermia, but he has sperm which is confirmed by section, difficulty in sexual intercourse, difficulty in ejaculation, erectile dysfunction, etc., it is recommended to receive IVF to successfully conceive.

4. In vitro fertilization with intracytoplasmic sperm injection (IVF-ICSI)

In vitro fertilization with intracytoplasmic sperm injection (IVF-ICSI) is a step of combining the ovum with the sperm in the IVF procedure, directly injecting the sperm into the ovum cell to increase fertilization rate. This technique is suitable for male azoospermia and sperm cell must be taken from testes or epididymis, oligospermia, asthenospermia, sperm after frozen, teratospermia, high sperm viscous and poor penetration, severe anti-sperm antibodies, excessively thick ovum zona pellucida, and poorly fertilized rate for unknown reason, ovum after frozen, in vitro matured ovum, and those who receive PGD or PGS.

5. In vitro fertilization (IVF) combined with preimplantation genetic screening (PGS) or preimplantation genetic diagnosis (PGD)

Preimplantation Genetic Screening (PGS) is a method of sectioning of embryonic cells after the fifth day (blastocyst stage) after IVF treatment, and DNA amplification of the embryonic cells is utilized. The next generation sequence is to perform rapid genome-wide sequencing, to detect whether the chromosome number or structure of the embryo is normal, and to select embryo transfer without abnormality to increase the pregnancy rate. It is applicable to habitual abortion, family history of chromosomal abnormalities, multiple IVF failures, or old age women with higher probability of embryonic chromosome abnormalities.

Preimplantation genetic diagnosis (PGD) uses embryonic sectioning, DNA amplification and other techniques after IVF treatment. It is suitable for patients with familial genetic diseases and genetic abnormalities. It use customized probes to detect whether the embryo carries the gene of hereditary disease and chooses embryo transfer without abnormality to increase the pregnancy rate.

VII. Factors affecting the effectiveness of infertility treatment

In addition to the maternal age, and normality of the embryo and uterus, the environment in which the embryo is implanted, grown, and developed in the uterine cavity is also a key factor.

1. A proper evaluation of infertility

A proper evaluation of infertility is the way to discover the etiology of infertility and subsequent treatment modalities. It is necessary for both males and females to have detailed examinations for infertility to treat infertility.

2. The quality of sperms and ova

The quality of sperms and ova is one of the important influential factors in the success rates of pregnancy and the bedding of embryo. A good life habit is helpful in improving the quality of sperm and ova, including avoidance from uses of cigarettes, alcohol, recreational drug, etc., proper adjustment of workload, emotional stress and pressure, balanced and nutritional diets, and physical fitting.The number and quality of the ovum depends on the age of females. Females with older age have higher risk of decreased number of the ovum and abnormal chromosome due to ovarian failure.Gene-related infertile males and females are required to receive in-vitro fertilization with chromosome examination and gene diagnosis to select normal embryo and increase pregnancy rates.

3. Maintenance of a good environment of fertilization, bedding and development of embryo

Single sexual partner and habits of correct and proper cleaning of perineum can effectively reduce the infection of female reproductive system and risk of pelvic inflammation diseases. Patient with endometriosis or ovarian tumors should have proper evaluations and treatments to treat the infertility caused by adhesion of pelvic organs.Females with endometrial polyps or submucosal uterus myoma are recommended to undergo hysteroscopic tumor resection to increase success rates of embryo bedding.In addition to maternal age, the morphology of embryo and uterus is the key to normal environment of embryo bedding and growth.Females with no fertilization plan should have measures of contraception to reduce the risk of endometrial injuries and adhesion of uterus cavity.

The overt thinning of endometrium would have an adverse effect on the embryo bedding. According the prior studies and clinical experiences, the thickness of endometrium is required to be 8 mm to stabilize the bedding the fertilized egg. It is difficult for females with the endometrium less than 8 mm in thickness to be pregnant. For in-vitro fertilization, it is necessary to ensure the adequate thickness of endometrium before embryo implantation. Besides, the poor-controlled autoimmune diseases or metabolic diseases would result in the abnormal vasculatures and hypoperfusion in the uterus, chronic inflammation of uterus cavity, and thrombus formation, which lead to difficult bedding of embryo and inadequate blood supply. Maternal systemic lupus erythematosus or autoimmune thyroid dysfunction produces the antibody, which may be transferred through placenta and affect the fetus, causing atrioventricular conduction delay or thyroid dysfunction of the fetus.

In the second and third trimesters of pregnancy, the abnormal uterus contraction, gestational hypertension and preeclampsia affect the fetal and maternal health. How to maintain a good environment of the uterus cavity is vital to the health of the maternal body and neonates.