Infertility

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Sanjana Nethagani, M.B.B.S.[3]

Infertility primarily refers to the biological inability of a man or a woman to contribute to conception. It is defined as the failure to conceive after 1 or more years of unprotected sex. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term. There are many biological causes of infertility, some which may be bypassed with medical intervention. Women who are fertile experience a natural period of fertility before and during ovulation, and they are naturally infertile during the rest of the menstrual cycle. Fertility awareness methods are used to discern when these changes occur; by tracking changes in cervical mucus or basal body temperature.

Infertility has always led to social and emotional impairment for the woman involved. In addition, most cultures had their own myths and beliefs around fertility which made it even more challenging for women who could not conceive. The male role in infertility was only brought to light after the discovery of the spermatozoa.

Infertility is broadly classified into primary and secondary, where primary infertility is seen in women who have never conceived and secondary infertility is the inability to conceive after a previous pregnancy. Infertility can also be classified based on etiology such as endocrine, metabolic, genetic etc.

Disorders of ovulation make up at least 25% of the cases of infertility worldwide, according to a study done by WHO. Other pathologies such as genital tract infections, pelvic inflammatory disease, endometriosis make up the bulk of female infertility cases.

A wide range of physical and emotional factors can cause infertility. Infertility may be due to problems in the woman, man, or both. The most common cause of male infertility is sperm abnormalities such as oligospermia, azoospermia etc. Causes of infertility in females are divided into endocrine, ovarian, tubal, uterine, cervical and other anatomical defects.

There are strict definitions of infertility used by many doctors. However, there are also similar terms, e.g. subfertility for a more benign condition and fecundity for the natural improbability to conceive.

Infertility is more commonly seen in women >35 years of age. Associated conditions such as diabetes mellitus, endometriosis, PCOS also cause infertility in women.

Old age is the most important non modifiable risk factor determining fertility in women. Other risk factors include being overweight, endocrine disorders such as diabetes mellitus and PCOS. Smoking and drug abuse may also cause infertility.

Routine screening for infertility is not usually done, but fertility evaluation is recommended for women who are above 35 years of age and have not already conceived.

Infertility may cause marital discord among couples who wish to conceive. Infertility treatment such as IVF and AI are associated with risks such as multiple gestations and preterm labour. Prognosis is generally good in women who receive treatment for infertility.

Diagnosis of infertility usually involves a battery of tests including blood and urine tests along with radiographic imaging. Hormone levels are checked via blood and urine tests whereas patency and abnormalities in the genital tract are detected with hysteroscopy, hysterosalpingography and gynecologic ultrasonography.

Treatment of infertility usually starts with medication. In vitro fertilization (IVF) in addition to various forms and developments of it (ICSI, ZIFT, GIFT) is another solution. All these come under the gamut of assisted reproductive technology. They all include that the fertilization takes place outside the body. On the other hand, an insemination can make a fertilization inside the body. Other techniques are assisted hatching and PGD.

Surgical therapy mainly aims at resolving any anatomical defects in the genital tract. Tuboplasty is done for any defects in the fallopian tubes such as scarring due to pelvic inflammatory disease or tuberculosis. When fibroids are the cause of infertility, myomectomy can be done. Other surgical methods include metroplasty, polypectomy, adhesiolysis.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Sanjana Nethagani, M.B.B.S.[3]

Infertility has always been emotionally distressing and a cause of social stigma for the woman involved. Many cultures had their own explanations and beliefs around infertility.

• Historically, infertility was associated with social stigma and embarrassment for women particularly.
• A lot of cultures encouraged having a second wife as to have offspring.^[1]
• The value of a woman was placed almost entirely on how fertile she was and how many children she could bear.
• The discourse around infertility changed from a religion-centric view to a scientific view after the discovery of spermatozoa and other advancements in modern medicine.^[2]

• Artificial insemination was first discovered by Lazzaro Spallanzani in Italy. His first experiment in artificial insemination was successfully performed on dogs.^[3]
• The first successful case of artificial insemination in humans was performed by Dr. John Hunter, a Scottish surgeon. ^[4]
• The first “test tube baby” was born with the help of IVF successfully performed by Robert G. Edwards and Patrick Steptoe in 1978. ^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Sanjana Nethagani, M.B.B.S.[3]

Infertility is broadly classified into primary and secondary, where primary infertility is seen in women who have never conceived and secondary infertility is the inability to conceive after a previous pregnancy. Infertility can also be classified based on etiology such as endocrine, metabolic, genetic etc

• It refers to couples who have never been able to conceive.
• Primary infertility also includes women conceived but have had regular miscarriages.

• It refers to difficulty conceiving after already having conceived and carried a normal pregnancy. Technically, secondary infertility is not present if there has been a change of partners.

Other causes of infertility are male infertility, systemic medical illnesses and unexplained infertility.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Sanjana Nethagani, M.B.B.S.[3]

Disorders of ovulation make up at least 25% of the cases of infertility worldwide, according to a study done by WHO. Other pathologies such as genital tract infections, pelvic inflammatory disease, endometriosis make up the bulk of female infertility cases.

• A decrease in sperm count^[1]
• Sperm being blocked from being released
• Sperm that do not work properly
• Genetic disease such as Klienefelter syndrome, Noonan syndrome and chromosome Y deletions.

• A fertilized egg or embryo does not survive once it sticks to the lining of the womb (uterus).^[2]
• The fertilized egg does not attach to the lining of the uterus
• The eggs cannot move from the ovaries to the womb
• The ovaries have problems producing egg
• Hormonal imbalance such as hyperprolactinemia, hypothyroidism, diabetes mellitus, PCOS which interfere with fertility.

• Endometriosis
• Pelvic inflammatory disease
• Diabetes mellitus
• Hypothyroidism

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Sanjana Nethagani, M.B.B.S.[3]

A wide range of physical and emotional factors can cause infertility. Infertility may be due to problems in the woman, man, or both.

Factors that can cause male as well as female infertility are:^[1]

• Genetic
• General factors
  • Diabetes mellitus, thyroid disorders, adrenal disease
• Hypothalamic-pituitary factors:
  • Kallmann syndrome
  • Hyperprolactinemia
  • Hypopituitarism

• Female infertility may be caused by:

• Autoimmune disorders, such as antiphospholipid syndrome (APS)
• Cancer or tumor
• Clotting disorders
• Diabetes
• Drug Side Effect- Cyclophosphamide, Norgestimate and Ethinyl estradiol
• Growths (such as fibroids or polyps) in the uterus and cervix
• Birth defects that affect the reproductive tract
• Excessive exercising
• Eating disorders or poor nutrition
• Use of certain medications, including chemotherapy drugs
• Drinking too much alcohol
• Obesity
• Older age
• Ovarian cysts and polycystic ovary syndrome (PCOS)
• Pelvic infection or pelvic inflammatory disease (PID)
• Scarring from sexually transmitted infection or endometriosis
• Thyroid disease
• Too little or too much hormones

• Male infertility can be caused by:

• Environmental pollutants
• Being in high heat for prolonged periods
• Birth defects
• Heavy use of alcohol, marijuana or cocaine
• Too little or too much hormones
• Impotence
• Infection
• Older age
• Cancer treatments, including chemotherapy and radiation
• Scarring from sexually transmitted diseases, injury, or surgery
• Retrograde ejaculation
• Smoking
• Use of certain drugs, such as cimetidine, spironolactone, and nitrofurantoin

  • Other drugs– Cyclophosphamide, Sulfasalazine, Valganciclovir

• In healthy couples under age 30 who have sex regularly, the chance of getting pregnant is about 25 – 30% per month.
• A woman’s peak fertility occurs in her early 20s.
• After age 35 (and especially 40), the chances that a woman can get pregnant drops considerably.

• In some cases, both the man and woman may be infertile or sub-fertile, and the couple’s infertility arises from the combination of these conditions.
• In other cases, the cause is suspected to be immunological or genetic; it may be that each partner is independently fertile but the couple cannot conceive together without assistance.

• In about 15% of cases the infertility investigation will show no abnormalities. In these cases abnormalities are likely to be present but not detected by current methods. Possible problems could be that the egg is not released at the optimum time for fertilization, that it may not enter the fallopian tube, sperm may not be able to reach the egg, fertilization may fail to occur, transport of the zygote may be disturbed, or implantation fails.
• It is increasingly recognized that egg quality is of critical importance and women of advanced maternal age have eggs of reduced capacity for normal and successful fertilization.

• Desogestrel and Ethinyl Estradiol
• Valganciclovir hydrochloride

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Sanjana Nethagani, M.B.B.S.[3]

There are strict definitions of infertility used by many doctors. However, there are also similar terms, e.g. subfertility for a more benign condition and fecundity for the natural improbability to conceive.

Reproductive endocrinologists, the doctors specializing in infertility, consider a couple to be infertile if:^[1]

• The couple has not conceived after 12 months of contraceptive-free intercourse if the female is under the age of 34
• The couple has not conceived after 6 months of contraceptive-free intercourse if the female is over the age of 35 (declining egg quality of females over the age of 35 account for the age-based discrepancy as when to seek medical intervention)
• The female is incapable of carrying a pregnancy to term.

• A couple that has tried unsuccessfully to have a child for a year or more is said to be subfertile.
• The couple’s fecundability rate is approximately 3-5%. Many of its causes are the same as those of infertility.
• Such causes could be endometriosis, or polycystic ovarian syndrome.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Sanjana Nethagani, M.B.B.S.[3]

Infertility is more commonly seen in women >40 years of age. Women who are >35 have a decline in fertility.

Prevalence of infertility varies depending on if the infertility is classified as primary or secondary infertility^[1].

• Some studies state that around 25% of couples globally are faced with infertility and childlessness. This number varies according to geographical region, age bracket and other such factors. ^[2]
• In the US, it is estimated that around 12.5% of women between the ages of 20-44 have reported being infertile according to the National Health and Nutrition Examination survey ^[3]
• In general, fertility among women declines with age. Age related decline is seen in women around 32 years of age, after which there is a sharper decline in fertility and fecundity. ^[1]
• male infertility accounts for around 20-30% of the global cases of infertility. ^[4]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Sanjana Nethagani, M.B.B.S.[3]

Advanced age is the most important modifiable risk factor for women with infertility. Other risk factors include diabetes mellitus, hypothyroidism, PCOS etc.

Several factors play a role in infertility among women, such as:^[1]

• Advanced age is the most common risk factor. Women who are over the age of 30 have a declining ovarian reserve. ^[2]
• Chronic diseases such as diabetes, hyperthyroidism, hypertension etc also may cause infertility.^[3]
• Obesity is linked to infertility via various pathways, including peripheral aromatisation of estrogens leading to increased testosterone production which decreases gonadotropin secretion.^[4]
• Being underweight also causes infertility as evidenced by the female athlete triad. Low body weight is linked to infertility and sub fertility due to functional hypothalamic amenorrhea.
• Hormonal imbalance can cause infertility. The most common cause of hormonal imbalance is PCOS.
• Environmental hazards such as smoking, alcohol abuse, drug abuse etc.
• Untreated or improperly treated sexually transmitted infections which can lead to pelvic inflammatory disease and cause adhesions, synechiae and scarring.
• Previous pelvic or abdominal surgery.
• Endometriosis and adenomyosis
• Uterine fibroids
• High levels of stress among women have been associated with decreased fertility. ^[5]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Sanjana Nethagani, M.B.B.S.[3]

Common complications of infertility treatment include multiple gestations, gestational diabetes, etc. If left untreated, infertility may cause marital discord and psychological issues in the couple.

• Infertility can have a big emotional impact on both of the involved partners.^[1]
• Depression, anxiety, and marriage problems may occur.
• Fertility induction using drugs such as clomiphene or assisted reproductive technology may cause multiple gestations and premature labor.^[2]
• Therapies such as IVF and Assisted reproductive technology are expensive and are a financial strain on couples who wish to conceive.

• As many as 1 in 5 couples diagnosed with infertility eventually become pregnant without treatment.
• More than half of the couples with infertility become pregnant after treatment, not including advanced techniques such as in vitro fertilization (IVF).

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Infertility has an impact on couples ethically, psychologically and socially.

There are several ethical issues associated with infertility and its treatment.

• High-cost treatments are out of financial reach for some couples.
• There is debate over whether health insurance companies should include cover for infertility treatment.
• There is some grey area around the legality and status of embryos fertilized in vitro and not transferred in vivo.^[1]
• Anti-abortion lobby groups oppose the destruction of embryos not transferred in vivo as they believe in the personhood status of embryos, regardless of transfer in vivo or not.
• IVF and other fertility treatments have resulted in an increase in multiple births, provoking ethical analysis because of the link between multiple pregnancies,premature birth, and a host of health problems and financial strain due to the same on couples.
• Religious leaders’ have differing opinions on fertility treatments. ^[2]
• Infertility caused by DNA defects on the Y chromosome are passed on from father to son. Natural selection is the primary error correction mechanism that prevents random mutations on the Y chromosome, it also prevents the same defect from passing on to the next generation. Fertility treatments for men with abnormal sperm (in particular ICSI) only defer the underlying problem to the next male generation.

• Infertility may have profound psychological effects.
• Both partners involved are prone to being anxious about conceiving, which itself plays a role in increasing sexual dysfunction.
• Marital discord often develops in infertile couples, especially when under pressure to make medical decisions.
• Women trying to conceive often have clinical depression rates similar to women who have heart disease or cancer^[3].
• Even couples undertaking IVF face considerable stress, especially the female partner.

• In many cultures, inability to conceive bears a stigma.
• In certain social groups, couples face rejection due to not conceiving and bearing children. Societal rejection may cause depression or anxiety in couples involved.

• There are legal ramifications around infertility as well. Ownership of frozen embryos is a much debated issue, particularly after the time of storage has lapsed. ^[4]
• Some courts have ruled to grant frozen embryos all legal rights which are granted to living humans since they have the potential to be born.^[5]
• Some other courts have granted frozen embryos a property status, which means they are similar to any other human tissue as property.
• The third position some courts have ruled on is that frozen embryos deserve certain, but not all rights as they are neither property nor full fledged human beings before birth.
• Around 4 million workers in the U.S. used the Family and Medical Leave Act (FMLA) in 2004 to care for a child, parent or spouse, or because of their own personal illness. Many treatments for infertility, including diagnostic tests, surgery and therapy for depression, can qualify one for FMLA leave.

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