Causes of Infertility

These affect how you ovulate.

• PCOS - polycystic ovary syndrome: A common cause of infertility where ovulation may not happen regularly.
• POI - premature ovarian insufficiency: when ovaries have fewer eggs than normal, causing irregular or absent periods, often before age 40.
• Hormonal dysfunction:
  • Thyroid disorders (hypothyroidism or hyperthyroidism): abnormal thyroid hormones' levels can lead to a disruption of the menstrual cycle and ovulation.
  • Absence of any periods (hypothalamic amenorrhea), caused by stress, heavy exercise, very low weight, or eating disorders.
  • Abnormally high prolactin levels (hyperprolactinemia): prolactin is a hormone that can block ovulation, if elevated outside of pregnancy or breastfeeding.

Meaning, the Fallopian tubes are blocked, damaged or non-existent, and that makes it hard or impossible for the egg and sperm to meet.

• Previous tubal ligation (sterilization procedure)
• Pelvic inflammatory disease (PID), an infection of the female reproductive organs, including the uterus, fallopian tubes, and ovaries
• Previous STIs, such as chlamydia or gonorrhea
• Hydrosalpinx: the tube(s) is damaged, fluid-filled, often from old infection or prior PID
• Endometriosis (see below)
• Prior ectopic pregnancy which may lead to partial or complete tubal damage or loss
• Prior surgery such as appendectomy, C-section, ovarian cystectomy, or myomectomy, can cause adhesions that entrap or block the tubes
• Other less common conditions:
  • Tuberculosis
  • Congenital malformations
  • Previous radiation therapy to pelvis
  • Salpingitis isthmica nodosa, a nodular thickening of the fallopian tube wall
  • Autoimmune diseases, such as lupus (these may indirectly affect tubal function through inflammation)
• Unexplained tubal obstruction of unknown ("idiopathic") origin: in some women, tubal blockage is discovered during HSG¹ or laparoscopy without an obvious history or known cause.

These cause some physical problems to happen in the uterus, preventing or stopping a pregnancy.

• Fibroids (also called leiomyomas or myomas): non-cancerous tumors made of muscle and connective tissue that grow in the uterus.

  There are 4 different "locations" for fibroids, and they do not always impact fertility. Submucosal fibroids (located just under the uterine lining) are the most likely to cause fertility problems by distorting the uterine cavity, potentially blocking the tubes or interfering with embryo implantation.

  These can be completely painless, but painful ones (or those suspected of impairing fertility) can be found and removed via laparoscopy, or hysteroscopy.

• Endometrial (or uterine) polyps: they are benign (non-cancerous) overgrowths of endometrial tissue (the uterine lining), ranging from a few millimeters to several centimeters.

  Similar to fibroids, they can impact fertility, for instance when blocking or distorting the uterine cavity, interfering with embryo implantation, or causing chronic inflammation.

  They can also be removed via laparoscopy, as well as via a "hysteroscopy" or during a D&C⁴.

• Uterine septum: a congenital (present at birth) malformation where a band of fibrous or muscular tissue divides the uterine cavity, partially or completely.

  Often symptomless, and discovered during infertility investigations or pregnancy complications.

  Generally fixed via hysteroscopic surgery.

• Uterine adhesions (Asherman's syndrome): scar tissue inside the uterus coming from surgery (like D&C or C-section) or an infection.

  It can cause no period or light periods, uterine distortions, implantation difficulty or failure, or miscarriage.

  Generally removed via hysteroscopic surgery.

• Cervical stenosis: the cervix becomes narrowed or completely blocked, either partially or fully: this interferes with sperm entry or embryo transfer.

  Can be asymptomatic, or cause light/absent/painful periods, chronic pelvic pain or pressure, difficulty or pain with IUI⁵ or embryo transfer.

  Can be congenital, or caused by surgery, menopause, radiation therapy, chronic infection, endometriosis, or fibroids.

  Depending on the cause medications or surgery can be used; mechanical means are however often used for dilation prior to procedures.

• Hostile cervical mucus refers to cervical mucus that is unfavorable or inhospitable to sperm survival and movement.

  Mucus can be hostile because of an inappropriate consistency, abnormal pH level, hormonal imbalances, infections, or medication side effects.

  When cervical mucus is abnormal, it may prevent sperm from entering the uterus or even destroy the sperm before they can reach the egg.

2 related but distinct conditions involving the uterus. The exact cause is still not very well understood.

• In endometriosis, tissue similar to the uterus lining (endometrium) grows outside the uterus, which is abnormal. It is found on ovaries, tubes, ligaments, the pelvic lining, and sometimes even distant organs.
• In adenomyosis, the endometrial tissue grows into the muscular wall of the uterus (myometrium), which is abnormal. It is only found in the uterus muscle.
• How they affect fertility:

  Endometriosis causes inflammation and scar tissue that can distort pelvic anatomy, but it also can impact egg quality, uterine receptivity, and embryo implantation.

  Adenomyosis can alter uterine function and cause contractions, and also interfere with embryo implantation.

• Symptoms: for both, pelvic pain, cramping, and infertility are common. Endometriosis also can entail painful periods, painful intercourse, and bowel or bladder issues.
• Diagnosis and treatment: unfortunately, neither of these conditions is easily diagnosed or treated/fixed.

  Endometriosis is often diagnosed based on symptoms corroborated by a pelvic exam, imaging (ultrasound, MRI⁶, or ReceptivaDx⁷, which is not 100% accurate), or a combination of the above. But it can only be truly confirmed – and removed – by laparoscopy.

  Adenomyosis is even harder to diagnose: it is usually suspected based on symptoms and imaging (MRI works best), but definitive diagnosis is sometimes only given after hysterectomy (surgical removal of the uterus).

  Managing symptoms is available, but is not necessarily efficient in the context of infertility.

  Beyond laparoscopic excision (removal) of endo tissues (which may also need to happen several times over the years), hormonal down-regulation (e.g., with Lupron Depot or Orilissa) is commonly used in the context of ART for both conditions: this essentially tones down all inflammation and hormonal activity, creating a quieter environment for embryo transfer.

  For adenomyosis, adenomyomectomy (surgical removal of parts of the tissues) is sometimes an option, but not common. The only permanent treatment is removing the uterus completely – which in infertility cases, would not help at all – leaving hormonal down-regulation in most cases as the primary tool.

A natural process that typically begins around age 35, when the number and quality of a woman's eggs start to decline more quickly.

• Very sadly, age is the one factor we can't change, and its impact on female fertility is far greater than most people realize (even if sperm can also lessen in quality).
• We can however (up to a degree), work on egg quality, with certain medications, supplements and other tools.

Check out our "Improving egg quality: myth or reality?" article

(coming soon!)

A number of conditions or issues in males' reproductive system and hormonal balance can lead to difficulties in conceiving. Most now have treatments that can partially fix the issue, or tools in the embryology lab that can help bypass some of these issues.

• Low sperm count (oligospermia): this is simply how many "swimmers" are counted in one sample ejaculate.

  Many fertility specialists define a normal sperm count as being ≥ 39 million per ejaculate, but the WHO⁸ recently revised their guidelines to ≥ 16 million/mL.

  39 million seems like a lot … and more than enough. However, not all sperm have good motility, morphology, or DNA⁹ integrity – and the journey from ejaculation to egg is quite the obstacle course during natural conception, narrowing down each individual one's chances significantly. Indeed, they need to: find the cervix, go past the cervix and its mucus, go up the uterus, orient themselves towards one tube or the other, and actually find the right tube containing the egg, and then … beauty pageant 🏆: only the best one gets in!

• Poor motility (asthenozoospermia): motility refers to how well sperm move: to reach and fertilize an egg in the uterus, sperm need to swim forward actively and efficiently.

  Similarly, normal motility is defined as being ≥ 42% motile sperm by the WHO.

  If sperm can't move well, they can't reach the egg, and this causes fertility issues.

• Abnormal morphology (teratozoospermia): if less than 4% of the sperm have a "normal form", then morphology is said to be abnormal.

  Morphology is about how sperm look under a microscope: both their shape and structure. A sperm with abnormal morphology may struggle to penetrate the egg.

• Azoospermia: this means there are no sperm present in the ejaculate. Depending on the cause, there can be some hope:
  • Sperm is being made, but is blocked from reaching the semen for physiological reasons, there can be surgical repair, and/or use of specialized retrieval techniques like TESE¹⁰/TESA.
  • There is little or no sperm production at all: some treatments are possible (medications, supplement, TESE), but there is a possibility that donor sperm may need to be considered.
• Sperm fragmentation: this is when there are breaks or damage in the DNA inside the sperm. It can affect fertilization, embryo development, and pregnancy outcomes.

  Similar to sperm motility and morphology, some lifestyle & health improvements, and/or some supplements, can help reduce fragmentation.

  A variation of ICSI¹¹, called "PICSI", can also be used. In short, before being injected in the egg, the sperm is selected based on its ability to bind to hyaluronic acid (a substance found naturally around the egg), which tends to identify healthier, more mature sperm with better DNA integrity.

  A specific procedure, TESA or TESE ("Testicular Sperm Aspiration", where sperm is taken directly from the testicle where it may have less DNA damage than ejaculated sperm) can also help in severe cases.

• Varicocele: this is like varicose veins, but in the scrotum; veins around the testicle become enlarged and twisted.

  This can lead to increased heat around the testicle, reduced sperm production, lower sperm quality (count, motility, morphology).

  Common cause of male infertility, and can often be treated with a minor surgery if needed.

• Ejaculatory dysfunction: basically, this entails problems with the release of semen during ejaculation, which can affect fertility.
• Hormonal imbalances (e.g., low testosterone, high prolactin): Just like women, men need balanced hormones to produce healthy, good-quality sperm. Hormonal imbalances in men can reduce sperm production or quality.
• Genetic conditions (Klinefelter syndrome, Y-chromosome microdeletions) that often cause very low or no sperm production.
• Previous medical treatment (such as cancer treatment) leading to some of the above as well.

(I am working to expand some of this section in our "Infertility 201" chapter, which will be released later this year!)

For the female:

• Autoimmune conditions, such as lupus, antiphospholipid syndrome, Hashimoto's, dysfunctional immune system, allergies or asthma, etc.
• Chronic endometritis, which is a uterine inflammation detected via a biopsy of the uterus lining (called CD138 immunostaining). Treatment consists of one or more antibiotics course(s).
• Thin endometrium, which is when the uterus has a poor lining growth, not allowing for an embryo to attach.
• Luteal phase defect, which is when the second half of the menstrual cycle is shorter than normal, or the uterine lining doesn't develop adequately for implantation.
• Resistant ovary syndrome or FSH¹² receptor mutations, making the production of eggs difficult.
• HPA axis dysfunction: the "Hypothalamic-Pituitary-Adrenal" (HPA) axis is a key system that controls the body's response to stress. When disrupted, it can suppress reproductive hormones and interfere with ovulation.
• Post-birth control hypothalamic suppression: after stopping hormonal birth control the brain's hypothalamus (what controls the menstrual cycle) may take time to "wake up" and resume normal signaling.

For the male:

• Obstructive azoospermia (e.g., congenital absence of vas deferens in cystic fibrosis carriers)
• Testicular failure (from chemotherapy, radiation, mumps orchitis)
• Anti-sperm antibodies present in the male or female system and destroying the sperm
• Retrograde ejaculation, where semen flows backward into the bladder instead of exiting through the tip of the penis
• Sertoli cell-only syndrome, which is when the testes have the "helper" cells (Sertoli cells) but are missing the actual "builder" cells (germ cells) needed to produce sperm
• Genetic karyotype issues: some men may have extra chromosomes, missing parts of chromosomes, or rearranged chromosomes (called translocations), which can affect sperm production or embryo viability

Sometimes, one of the partners will have multiple contributing factors, or both partners have contributing factors, making solving the equation more complicated. It is then truly a detective work, having to explore all possible avenues on both sides, progressively eliminating potential causes, and sometimes treating several issues at once.

Check out my "Me and my Infertility Story" article, where I go through my very difficult and time-consuming journey to find out all my contributing factors.

[Article coming soon!]

Sometimes, some other factors (in one or both partners) can also be the cause for some of the infertility factors mentioned in this chapter – and some can be longer to address than others. They can include:

• Lifestyle choices (obesity, smoking, heavy alcohol or drug use, extreme stress)
• Environmental toxins (e.g., pesticides, endocrine disruptors)
• STIs or undiagnosed infections
• Incompatible HLA¹³/killer cell mismatch (controversial in immunologic infertility)
• Chromosomal translocations
• Mitochondrial dysfunction (egg or sperm)

… and sometimes no clear diagnosis can be given after a complete workup.