What is Infertility?

Infertility is a medical condition involving both genders rather than an individual. It is defined as inability to conceive after 12 months of regular intercourse without the use of contraception in women younger than 35 years of age and inability to conceive after 6 months of regular intercourse without the use of contraception in women with age of 35 and above.

Fertility (also called fecundity) refers to the capacity to conceive and produce offspring.

Fecundability is the probability of achieving a pregnancy in a single menstrual cycle. Subfecundity is a decrease in fecundability.

Causes of Female Infertility

In a study conducted by World Health Organization on 8500 infertile couples, infertility due to pathologies in females was reported to be 37 percent in developed countries. Male factor infertility was 8 percent. Both male and female factor of infertility was present in 35 percent couples. The remaining couples had inexplicable infertility or became gravid during the study. The most common identifiable female factors, which accounted for 81% of female sterility, were:

Ovulatory disorders25 percent
Endometriosis15 percent
Pelvic adhesions12 percent
Tubal blockage11 percent
Other tubal abnormalities11 percent
Hyperprolactinemia7 percent

Advance female age has also been a strong factor affecting female fertility. It has been observed that elderly couples faced difficulty in getting pregnant when compared with younger couples.

Both maternal as well as paternal age affects the pregnancy. Increasing the age of parents can also contribute chromosomal/congenital anomalies. The decrease in coitus in advanced age also affects the fertility factor.

Infertility

Ovarian Causes of Female Infertility

Here we discuss the causes of infertility in women originating from ovaries:

Ovulatory disorders

Oligoovulation (infrequent ovulation) or anovulation (absent ovulation) both can lead to infertility, women who experience regular menstrual cycles and associated symptoms like breast tenderness, bloating, etc. are more likely to get pregnant than as compared with those who either don’t have regular cycles or have not menstrual cycles at all.

Causes of ovulatory dysfunction are as follows:

Primary hypothalamic-pituitary dysfunction

  • Immaturity at the onset of menarche or perimenopausal decline
  • Intense exercise
  • Eating disorders
  • Stress, Depression, psychiatric illness
  • Idiopathic hypogonadotropic hypogonadism
  • Hyperprolactinemia
  • Tumors, trauma, or radiation of the hypothalamic or pituitary area
  • Lactational amenorrhea
  • Kallmann syndrome
  • Pituitary adenoma or other pituitary tumors
  • Sheehan’s syndrome
  • Empty Sella syndrome
  • Lymphocytic (autoimmune diseases)

Other disorders

  • Polycystic ovary syndrome
  • Hyperthyroidism hypophysitis or hypothyroidism
  • Hormone-producing tumors (adrenal, ovarian)
  • Chronic liver or renal disease
  • Cushing’s disease
  • Congenital adrenal hyperplasia
  • Turner syndrome
  • Premature ovarian failure, due to autoimmune, genetic, surgical idiopathic, or related to drugs or radiation
  • Androgen insensitivity syndrome

Medications

  • Estrogen-progestin contraceptives
  • Progestins
  • Antidepressant and antipsychotic drugs
  • Corticosteroids
  • Chemotherapeutic agents
Infertility

Infertility

Oocyte aging

The advanced maternal age affects the quantity and quality of the oocytes, which ultimately leads to infertility.

Follicle depletion in women increases when they reach their mid-thirties. Other factors including smoking, radiation, chemotherapy and environmental factors also affect the number of follicles. Women with depleted follicles may have regular menstrual cycles but they will be infertile due to the poor quality of the oocytes. This loss of oocyte quality with advanced maternal age is thought to be due to the meiotic nondisjunction or age-related changes in granulosa cells surrounding the oocyte.

Ovarian Cysts

No clear evidence was gathered from studies that whether an ovarian cyst was responsible for the cause of infertility up to a significant level. Though it was found that surgical intervention in such cases was more harmful to the oocyte pool then the cyst itself. Studies performed showed that most of these cysts were endometriomas.

Fallopian Tube Abnormalities & Pelvic Adhesions

Tubal diseases and pathologies interfere with the normal transport of the sperm to the oocyte or the transport of the fertilized ovum from the tube to the uterus for implantation. The most common cause that leads to this condition is pelvic inflammatory disease, which can be due to infection from chlamydia or gonorrhea.

Other conditions like adhesions after surgery, endometriosis, pelvic tuberculosis, benign tumors, non-tubal infections (like, appendicitis, inflammatory bowel disease), salpingitis, radiation can also lead to improper transport of the sperm or the egg thus leading to infertility or improper implantation of the fertilized oocyte. It will either end up in ectopic pregnancy or spontaneous abortion. Proximal tubal pathology involving mucous plugging, debris or spasm of the fallopian tube ostium in the uterus are also among the causes of tubal pathologies leading to infertility.

Women who encounter distal tubal blockage will also hinder sperm transportation and decrease the chances of successful IVF. Sometimes, it leads to hydrosalpinges, which further leads to a retrograde flow of oocyte and tubal contents creating a hostile environment for the egg implantation and fertilization. Releasing the hydrosalpinx will increase the possibility of a successful IVF.

Female Reproductive System

Uterine Causes of Female Infertility

Infertility related to the uterus can be due to the reduced acceptability of the uterus or impaired implantation due to an anatomical pathology.

Uterine Leiomyomata

Uterine leiomyomata or uterine fibroids are benign smooth muscle tumors which lead to difficult or improper implantation of the fertilized egg in the endometrial wall, thus leading to infertility. Studies have shown a strong association between infertility and uterine fibroids. Further it is proven with the fact that infertility rates were lower and pregnancy rates went up when submucosal lesions were surgically removed. Thus, it was shown that submucosal or intracavity tumors when removed, it leads to an increase in pregnancy rates.

Uterine Anomalies

Uterine anomalies among which the mullerian anomaly is the most common leads to infertility due to both improper implantation of the fertilized egg or rapid loss of the implanted embryo due to the ineffective capacity of the uterine wall and the capacity to accommodate the implanted egg.

Septate uterus (a type of congenital uterine anomaly) has been seen to be linked to the poorest reproductive outcome. Other anomalies like endometrial polyps and adhesions from previous pregnancy-related curettage also have shown to affect the fertility.

Intrauterine Adhesions

Intrauterine adhesions due to pelvic inflammatory disease, chronic endometritis, pelvic tuberculosis, previous surgery or curettage also leads to infertility.

Luteal Phase Defect

Luteal phase defect refers to the abnormality when there is improper release of progesterone during the luteal phase which is important for the implantation of the fertilized oocyte and growth of the endometrium to become more favorable for the implantation. Although in 2015, the American society of reproductive health concluded that progesterone no wonder is necessary for the growth of embryo and creating an attractive environment for the implantation, yet it has not been seen to effect infertility as an independent factor. So far, no treatment, definition or diagnostic tests are available for LPD.

Human Body Anatomy Uterus

Endometriosis

Endometriosis is when endometrial tissue is found at sites other than the uterus which can include myometrium, ovaries, pelvis and even abdominal cavity. Endometriosis leads to improper implantation and hostile anatomical environment for the fertilized egg. It also affects fertility, implantation and fertilization due to the release of cytokines and growth hormones by the endometrial tissue at unwanted and improper sites.

Cervical Factors

Normal mid-cycle cervical mucous facilitates the transport of sperms and providing appropriate pH for the survival of sperms. Congenital anomalies and cervical surgeries leading to defect in cervical mucous production impairs the transport of the sperms to the oocyte. Thus, it leads to infertility or decreased fertility rates.

Inherited Thrombophilia

Inherited thrombophilia (including factor V Leiden deficiency, antithrombin III deficiency and lupus anticoagulant) is not seen to be independently related to infertility. Therefore, screening for these diseases or treating them while treating infertility has not been of much significance. However, some studies have shown its relation between inherited thrombophilia and recurrent IVF failures.

Immune Factors

Immune factors also contribute female infertility or pregnancy loss.

Antiphospholipid Syndrome

Antiphospholipid antibody syndrome (APS) is related to early pregnancy rejection or placental damage. Screening and workup depend on the family history and medical condition of the patient whether APS is the cause of early pregnancy loss or infertility.

Antibodies Unrelated to APS

Women with autoimmune disorders do encounter reduced fertility rates. Although there is no direct effect of these antibodies on fertilization or implantation.

  1. Premature ovarian failure has been linked with myasthenia gravis and systemic lupus erythematosus.
  2. Polyglandular syndrome type I and II are also associated with autoimmune oophoritis, which has been linked with infertility due to tubal pathologies.
  3. The effect of these syndromes on other endocrine glands which directly or indirectly affect fertilization and implantation.

Celiac Disease

Women with the untreated coeliac disease have an increased risk of reproductive health abnormalities including infertility, improper implantation, fertilization, miscarriages and intrauterine growth retardation.

Genetic Causes

Genetic abnormalities have been observed in infertile couples when compared with the general population. Most common abnormalities observed are Turner syndrome (45 XO) in female and Klinefelter syndrome (47XXY) in men.

Individual gene abnormalities associated with sterility are fragile X syndrome, Kallmann syndrome, Prader-Willi syndrome, Angelman syndrome, Beckwith Wideman syndrome.

 

Lifestyle Factors

Following factors have been observed to affect fertility and fecundability.

  • Smoking.
  • Excessive alcohol intake.
  • Stress.
  • Obesity.
  • Sexual habits – history of sexually transmitted diseases.
  • Recreational drugs.
  • Caffeine not more than a total of 200mg/day.
  • Environmental pollutants and toxicants.
  • Healthy dietary habits.
  • Strenuous exercise – women of BMI <25 should limit vigorous exercise < 5hrs/week.

References

  1. Wendy Kuohung, Mark D Hornstein, infertility, https://www.uptodate.com/contents/overview-of-infertility
  2. WHO Technical Report Series. Recent Advances in Medically Assisted Conception Number 820, 1992, pp 1-111.
  3. American College of Obstetricians and Gynecologists Committee on Gynecologic Practice and Practice Committee, Female age-related fertility decline. Committee Opinion No. 589, Fertil Steril. 2014;101(3):633. https://www.ncbi.nlm.nih.gov/pubmed/24559617
  4. Jick H, Porter J, Lancet Relation between smoking and age of natural menopause. Report from the Boston Collaborative Drug Surveillance Program, Boston University Medical Center. 1977;1(8026):1354. https://www.ncbi.nlm.nih.gov/pubmed/69066
  5. Broekmans FJ, Soules MR, Fauser BC, Ovarian aging: mechanisms and clinical consequences. Endocr Rev. 2009;30(5):465. Epub 2009 Jul 9. https://www.ncbi.nlm.nih.gov/pubmed/19589949
  6. Legendre G, Catala L, Morinière C, Lacoeuille C, Boussion F, Sentilhes L, Descamps P, Relationship between ovarian cysts and infertility: what surgery and when? Fertil Steril. 2014;101(3):608. https://www.ncbi.nlm.nih.gov/pubmed/24559614
  7. Practice Committee of the American Society for Reproductive Medicine, Committee opinion: role of tubal surgery in the era of assisted reproductive technology, Fertil Steril. 2012;97(3):539. https://www.ncbi.nlm.nih.gov/pubmed/22285747
  8. Homer HA, Li TC, Cooke ID, The septate uterus: a review of management and reproductive outcome. Fertil Steril. 2000;73(1):1. https://www.ncbi.nlm.nih.gov/pubmed/10632403
  9. Practice Committee of the American Society for Reproductive Medicine. Current clinical irrelevance of luteal phase deficiency: a committee opinion, Fertil Steril. 2015;103(4): e27, https://www.ncbi.nlm.nih.gov/pubmed/25681857
  10. Casadei L, Puca F, Privitera L, Zamaro V, Emidi E, Inherited thrombophilia in infertile women: implication in unexplained infertility. Fertil Steril. 2010;94(2):755, https://www.ncbi.nlm.nih.gov/pubmed/19939360
  11. Cervera R, Balasch J, Bidirectional effects on autoimmunity and reproduction, Hum Reprod Update. 2008;14(4):359. https://www.ncbi.nlm.nih.gov/pubmed/18499707
  12. Kallen CB, Arici A, Immune testing in fertility practice: truth or deception? Curr Opin Obstet Gynecol. 2003;15(3):225. https://www.ncbi.nlm.nih.gov/pubmed/12858110
  13. Tersigni C, Castellani R, de Waure C, Fattorossi A, De Spirito M, Gasbarrini A, Scambia G, Di Simone N, Celiac disease and reproductive disorders: meta-analysis of epidemiologic associations and potential pathogenic mechanisms, Hum Reprod Update. 2014 Jul;20(4):582-593. Epub 2014 Mar 11. https://www.ncbi.nlm.nih.gov/pubmed/24619876
  14. Clementini E, Palka C, Iezzi I, Stuppia L, Guanciali-Franchi P, Tiboni GM, Prevalence of chromosomal abnormalities in 2078 infertile couples referred for assisted reproductive techniques, Hum Reprod. 2005;20(2):437. https://www.ncbi.nlm.nih.gov/pubmed/15567875