Infertility

APGO objectives

• • Define infertility
  • List the causes of male and female infertility
  • Describe the evaluation and initial management of an infertile couple
  • Describe the psychosocial issues associated with infertility
  • Describe the ethical issues confronted by patients with infertility
  • Identify the impact of genetic screening and testing on infertility associated treatments

 

Definition

In normally fertile couples, the chance for pregnancy is between 15 and 20% per cycle. 70% of all couples will attain a pregnancy within 6 months, and about 85% within a year.

Infertility is the inability to achieve a pregnancy with regular intercourse and no contraception within one year. For women age 35 or older, infertility begins at six months.

Infertility may be further described as “primary” or “secondary”

• • Primary Infertility means the patient has never been pregnant.
  • Secondary infertility means the patient has previously been pregnant, but has been unable to conceive again.

Causes of male and Female Infertility

Human reproduction requires coordination of several critical factors, including normal motile sperm, ovulation, and an unobstructed passage for the sperm to meet the egg.

Large numbers of sperm must be available at the cervix. They must be able to ascend through the cervix, uterus, and fallopian tubes and subsequently have the capacity to fertilize the egg.  Reduced numbers of functionally normal sperm is considered a “male factor,” and contributes to infertility in 30-40% of couples.

There are a variety of causes of male factor infertility.

Hypothalamic-Pituitary Disorders.

Normal spermatogenesis requires normal pituitary FSH and LH release.

Any disorder, which disrupts these signals, may lead to low sperm counts. Fewer than 15 million sperm per cc is considered low.

Hypothalamic Pituitary disorders that may cause low sperm counts include Idiopathic gonadotropin deficiency, Kallmann Syndrome (or congenital GnRH deficiency), Hypothalamic or Pituitary tumors, Chronic systemic illnesses, Hyperprolactinemia, certain Pharmacologic agents (Androgens, Estrogens, Glucocorticoids), and Obesity. 

The absence or destruction of functional testicular tissue may also cause male factor infertility.

Examples of such conditions include Klinefelter Syndrome (46XXY), Y chromosome microdeletions, Cryptorchidism, Pharmacologic agents (specifically chemotherapeutic agents), environmental toxins (such as smoking), infections (viral orchitis) and chronic systemic illnesses.

Finally, an unobstructed pathway from the epididymis to the urethral meatus is required for sperm to be emitted during intercourse.

Obstructions may be caused by epididymal cysts, congenital bilateral absence of the vas deferens, and infections such as gonorrhea and Chlamydia, which can cause scarring of the vas deference.

Erectile or ejaculatory problems such as spinal cord disease, retrograde ejaculation, or erectile dysfunction may cause male factor infertility, as can Kartagener syndrome (or primary ciliary dyskinesia).

For pregnancy to occur, sexual intercourse must take place shortly before or with ovulation. This timing is important because while normal sperm can remain functional inside the woman’s body for up to several days, the egg is only viable for fertilization for 12-24 hours after ovulation.

Ovulation Disorders

Ovulation problems are found in 20-40% of all infertile couples.  Problems may occur anywhere along the hypothalamic-pituitary-ovarian axis.

Hypothalamic Pituitary Disorders

Any condition interfering with the pituitary signals of FSH or LH, which are necessary for normal follicular recruitment and maturation, can lead to ovulation failure.

Examples include Idiopathic gonadotropin deficiency, Kallmann Syndrome (or congenital GnRH deficiency), Hypothalamic or Pituitary tumors, Chronic systemic illnesses, Hyperprolactinemia, Thyroid dysfunction, Pharmacologic agents (Androgens, Estrogens, Glucocorticoids), and Obesity.

Primary Ovarian disorders

Abnormally functioning ovarian tissue may also cause anovulation.

One example is premature ovarian insufficiency. This insufficiency may be linked to ovarian dysgenesis, prior use of chemotherapy, pelvic radiation therapy, or may be from a genetic predisposition.

Another leading cause of anovulatory infertility is polycystic ovary syndrome (or PCOS).  Although often considered a disorder of the ovary, this disease is the result of a complex pathophysiology involving the hypothalamus, pituitary, and ovary.

Passageway

Sperm need an unobstructed passage to meet the mature egg, as well as an optimal environment for the pregnancy to implant and grow.

This requires that the cervix is patent, the fallopian tubes are open and functional, and a normal uterine cavity, with a  receptive endometrium, is present. While cervical and uterine factors are infrequent causes of infertility, tubal and peritoneal pathology comprise 30-40% of all causes of infertility.

Cervical Factors

Cervical mucous functions as a healthy reservoir for sperm.

If the cervical glands are reduced in number due to previous cervical excision procedures (such as cone biopsies, or LEEP procedures) this may lead to reduced cervical mucous.  Cervical procedures may also cause scarring and cervical stenosis.

Uterine Factors

Fibroids may contribute to a uterine factor if they have a submucous component or distort the uterine cavity, as can endometrial polyps.

Uterine scarring (Asherman’s syndrome) or the absence of a uterus altogether (also known as Mayer-Rokitansky-Juster-Hauser syndrome) may cause uterine factor infertility.

Tubal and Peritoneal Pathology

Tubal and Peritoneal pathology together comprise a large proportion of the most common etiologies of infertility.

Pelvic inflammatory disease, tubo-ovarian abcess, and prior gonorrhea or chlamydia infections may cause long-term structural changes which ultimately compromise tubal integrity and function.

These abnormalities may not only lead to infertility, but may also increase the risk for ectopic pregnancy.  Conversely, a history of ectopic pregnancy should be a red flag to the practitioner for the possibility of underlying tubal disease, especially if tubal surgery (like a salpingostomy) is performed.

Endometriosis is a condition in which ectopic endometrial tissue is found on the peritoneum, ovary, tube, and sometimes in extrapelvic organs, and has a strong association with infertility.

With severe endometriosis, inflammation and scar tissue are considered major contributors to infertility. But with lesser degrees of endometriosis, it may be unclear whether the endometriosis is the cause for infertility, or rather represent an effect of some other factor that causes both the endometriosis and the infertility. Endometriosis is present in between 9 and 50% of infertile women.

Unexplained Infertility

In approximately 10-15% of all couples, there is no identifiable reason for infertility; these couples are considered to have unexplained infertility.  This doesn’t mean there is no cause. Rather, it means that whatever is causing the infertility is not yet detectable with our proven methods.

Some unexplained infertility relates to natural reproductive ageing, and the likely underlying etiologies relate to anomalies in gametes or implantation, for which there are no recognized validated tests.

Evaluation

The evaluation of an infertile couple should begin with a history and physical examination.

This includes the duration of infertility, the results of any prior testing or treatment, and the couple’s sexual history, particularly coital frequency.

For the female, inquiry is made about her obstetrical history (if any), gynecologic history, and menstrual history. Significant historical issues would include Galactorrhea, Hirsutism, Dyspareunia or Pelvic Pain

Noted are prior contraceptive use, any history of surgical procedures in the genital area or abdomen, and any STD history.

In addition to inquiring about any chronic medical illnesses or surgical history, family history is important. Evidence may be found for premature ovarian insufficiency, recurrent pregnancy loss, infertility, or other inheritable disorders.

It is important to also ask about the couples’ ethnic background in order to offer the most targeted preconception genetic screening tests

A Social History is obtained, to include an assessment of occupational exposures, use of alcohol, tobacco, or recreational drugs.

Current medications and allergies are noted.

Her physical exam will include height, weight, signs of androgen excess, examination of the thyroid, breasts, and a pelvic exam.

The male partner is generally referred to a urologist, or family physician with special skills in evaluating and treating male infertility.

Testing

The laboratory evaluation of the infertile couple involves an assessment of (1) Ovarian reserve (2) Tubal Patency (3) Assessment of ovulatory and Endocrine function and (4) Male factor (through a semen analysis)

Ovarian Reserve Testing

The most dynamic component of infertility testing is the assessment of ovarian reserve.  Ovarian reserve testing aims to determine the functional capacity of a woman’s remaining eggs.  It is important to remember that these tests do not tell whether a woman can or cannot get pregnant, they simply offer a guide for the practitioner in determining the likelihood of success with fertility treatment.

In general there are 3 validated tests for ovarian reserve.

The first day of a menstrual flow is day 1. On Day 3, blood tests are obtained, including an FSH, an estradiol, and an ultrasound scan for antral follicle count. An FSH level >10-20 IU/mL is considered abnormally high, suggesting the ovary is not responding normally. This is related to a poor chance for success with fertility treatment.  Transvaginal ultrasound is used to determine the number of antral follicles; low numbers of follicles correlates with poor ovarian reserve.

An elevated estradiol level (>60-80pgmL) in the presence of a normal FSH level is also associated with a poor prognosis for fertility treatments. Women with poor ovarian reserve tend to demonstrate premature follicle recruitment, which results in an abnormally high estradiol.

The cycle independent test for ovarian reserve is Antimullerian Hormone level (AMH).  AMH levels reflects the availability of primordial follicles, declines with advancing maternal age, and is absent at menopause. Age-adjusted normal values are used to evaluate the reproductive potential for infertile women.

Assessing Tubal Patency

There are several ways to assess tubal patency.

Hysterosalpingogram (HSG) utilizes real time fluoroscopy to image the passage of radio-opaque dye, injected through the uterus and out of the fallopian tubes.

Abnormal tubal morphology and the absence of free spill in to the peritoneal cavity can be helpful surrogate makers for the presence of extra-tubal pelvic adhesive disease.

More recently, Sono-hysterosalpingography with saline instillation has become a popular replacement for HSG.  This technique utilizes Doppler flow to visualize the tubes as they fill with saline; the presence of fluid in the cul de sac confirms patency of at least one fallopian tube.  If either of these tests are abnormal or indeterminate, the gold standard assessment of tubal patency is chromotubation at the time of laparoscopy.

Assessment of ovulatory function and Endocrine evaluation

The single best predictor that a woman is ovulating regularly is the presence of regular menstrual cycles every 21 to 35 days.  However, lab and imaging studies can also be done to confirm this.

In a woman with typical 28-30 day cycles, serum progesterone values on cycle days 21-24 should be elevated (>3 ng/dL), reflecting ovulation.

Progressive follicular growth and then collapse with ovulation can be visualized with serial transvaginal ultrasounds, confirming development and release of an egg.

Women with a history suggesting ovulatory dysfunction should undergo a thorough endocrine evaluation.  This includes serum TSH, FT4 and fasting prolactin levels, and targeted evaluation of male hormone levels in those women with complaints or signs of androgen excess.

Male Factor (Semen analysis)

The final component of the infertility evaluation is the semen analysis.

The male partner should provide a specimen after 2-5 days of abstinence.  The specimen is evaluated based on several criteria: volume, concentration, motility, and morphology.  Abnormalities in any one of these parameters may warrant additional evaluation by a urologist.

For instance, if no sperm is visualized (azoospermia), this may suggest gonadal failure (if normal volume ejaculate is present) or obstruction (if low volume ejaculate is present).  In the former, a serum FSH, E2, Testosterone and prolactin level should be obtained.  In the latter, a thorough physical exam should be performed by a urologist.

Preconception Counseling

Another important component of the initial evaluation is centered on preconception counseling.

Here, we have a unique opportunity to ensure adequate testing and preconception treatment to lower antenatal risks.  All pre-existing medical conditions should be assessed and optimized prior to pregnancy.  Titers for rubella and varicella should be obtained to determine ongoing immunity.

Finally, preconception genetic screening should be offered.  This screening can include an assessment of carrier status for cystic fibrosis, spinal muscular atrophy, thalassemia, and sickle cell disease, amongst others.

Management

In some cases, infertility is a result of a single major problem that is preventing pregnancy. In other cases, there are a number of minor factors, none of which will completely prevent pregnancy, but collectively may prolong the time to pregnancy.

The choice for fertility treatment is dependent on the couples’ initial evaluation.  Targeted treatment is best for isolated abnormalities, such as anovulation or azoospermia.  However, when more than one abnormality exists, or the evaluation is normal, a more empiric approach should be considered.  Consultation with a reproductive endocrinologist and infertility specialist is critical to determine the best treatment approach for couples with infertility.

Psychosocial issues associated with infertility

Numerous studies have shown increased symptoms of stress and anxiety in infertile women compared to the general population; not only is the diagnosis stressful, but chronic stress itself may reduce the success of fertility treatment (although the mechanism for this is poorly understood).

There are reasons for increased stress–the diagnosis of infertility can impact the couples’ relationship, their relationship with family and friends, their financial well-being, and potentially their outlook on life.  Ultimately, both diagnosis and treatment requires not only a physical commitment from the couple, but an emotional and financial commitment as well.

As the infertile couple is vulnerable to psychosocial issues, it is important for the practitioner to recognize signs of stress, depression, and anxiety.  Professional counseling, through a psychiatrist, psychologist, social worker, marriage or family therapist can be very helpful, and sometimes relationship or life-saving.  Consider referral for counseling if a patient or her partner experience any of the following:

• • Persistent feelings of sadness, guilt, or worthlessness
  • Social isolation
  • Loss of interest in usual activities and relationships
  • Depression
  • Agitation and or anxiety
  • Mood swings
  • Constant preoccupation with infertility
  • Marital problems
  • Difficulty with “scheduled” intercourse
  • Difficulty concentrating or remembering
  • Increased use of alcohol or drugs
  • Changes in appetite, weight, or sleep patterns
  • Thoughts about Suicide or Death

The ASRM patient website (ReproductiveFacts.org) provides several resources addressing the concerns of couples who have been given a diagnosis of infertility or who choose to pursue treatment.  Links to support groups and other national organizations, including Resolve (ww.resolve.org), American Fertility association (TheAFA.org), and the InterNational Counsil on infertility information dissemination, Inc (inciid.org), are also provided.

Ethical Issues in Reproductive Medicine

As the field of reproductive medicine evolves, so does the ethics of practice.

As humans, we value the right to reproduce, to build a family, and to take care of that family.  As practitioners, we have an obligation to understand the risks, benefits, and indications of treatment, and also the impact of treatment (or of no treatment) on the individual, the couple, and to society— we must use the available technologies in the most conscientious way.

The American Society of Reproductive Medicine provides guidance for tackling some of the most common ethical issues in practice.  Examples include:

• • Child rearing ability and the provision of fertility services
  • Embryo donation
  • Disparities in access to care
  • Disposition of abandoned embryos
  • Fertility treatment when the prognosis is poor or futile
  • Oocyte or embryo donation in women of advanced age
  • Financial compensation of oocyte donation
  • Use of pre-implantation genetic diagnosis, and
  • The use of family members as gamete donors and surrogates.

To help address these issues, infertility centers may collaborate with legal counsel, and draft office policies and procedures. It is important to ensure open dialogues with patients from the beginning of treatment to help in developing accurate expectations.

Impact of genetic screening and testing associated with infertility treatments

One of the most significant breakthroughs in reproductive medicine has been the evolution and usage of preimplantation genetic screening (PGS) and genetic diagnosis (PGD).

Preimplantation genetic screening refers to the testing for aneuploidy, or copy number variations of the autologous and sex chromosomes.

Preimplantation genetic diagnosis refers to testing for specific single gene disorders, if the parents are known carriers. Examples include Cystic Fibrosis, Spinal Muscular Atrophy, Thalassemia, Fragile X Syndrome, Sickle Cell anemia, Hereditary Breast/Ovarian cancer (BRCA1 and BRCA2).

The process of preimplantation genetic screening first requires the couple to undergo in vitro fertilization (IVF).  The female partner will take injections to stimulate follicle development, and then she subsequently undergoes an ultrasound guided oocyte retrieval.

After retrieval, the cohort of mature eggs are selected and injected with the male partner’s sperm through a process called intracytoplasmic sperm injection (ICSI).

While a number of embryo biopsy strategies have been used with varying degrees of success, most centers have moved towards genetic analysis at the blastocyst stage.

At this stage, the embryo contains hundreds of cells, which have further divided into what will ultimately become the fetus (inner cell mass) and the placenta (trophectoderm).  Several cells from the trophectoderm are biopsied and subjected to genetic analysis, which may include comparative genomic hybridization or next generation sequencing.

Although effective and reasonably safe, there are drawbacks to blastocyst biopsy. One is the possibility of placental mosaicism, which can reduce accuracy.

To counteract this risk, patients are still advised to undergo routine noninvasive prenatal screening during pregnancy (in cases of PGS) and consider invasive prenatal screening (in cases of PGD).

Another drawback to blastocyst biopsy is the possibility of having no embryos survive to the blastocyst stage in vitro, which means there would be no embryos to biopsy.

To counteract this risk, couples often “batch” their IVF cycles, meaning they undergo several cycles of IVF back-to-back to increase the pool of embryos available for analysis, especially if the female partner has decreased ovarian reserve.

Ultimately the current literature suggests that the chance of live birth after the transfer of a euploid embryo, regardless of the age of the recipient, is approximately 65%.

The implications and usage of PGD are clear:  couples can elect to reduce their risk of having a child with a disease that causes significant morbidity or mortality, if they themselves are carriers.

The indications for PGS however are still evolving.

Patient populations described to potentially benefit from this technology include couples in whom the female partner is of advanced maternal age, couples with a history of recurrent pregnancy loss or recurrent implantation failure following previous IVF cycles, and women with uterine anomalies or prior poor antenatal outcomes who require the lowest risk for multiple gestation.

 Resources

Practice Committee of the American Society for Reproductive Medicine.  Definitions of infertility and recurrent pregnancy loss: a committee opinion.  Fertility and Sterility 2013; 99:63

Practice Committee of the American Society for Reproductive Medicine.  Diagnostic evaluation of the infertile male: a committee opinion.  Fertility and Sterility 2015; 103:e18-25

Practice Committee of the American Society for Reproductive Medicine.  Diagnostic evaluation of the infertile female: a committee opinion.  Fertility and Sterility 2015; 103:e44-50

Practice Committee of the American Society for Reproductive Medicine.  Female Age Related fertility decline.  Fertility and Sterility 2014; 101:633-4

American Society for Reproductive Medicine.  Infertility Counseling and Support: When and Where to Find it.  Fact Sheet.  www.reproductivefacts.org

Ethics Committee of the American Society for Reproductive Medicine.  American Society for Reproductive Medicine.  (2011-2016) www.asrm.org/Ethics/Reports

Bayer, S. R., Alper, M.M., & Penzias, A.S. (2002).  The Boston IVF handbook of infertility: A practical guide for practitioners who care for infertile couples.  Boca Raton, FL: Parthenon. 

Dr. Nayak

Mullerian Anomalies

Jehnsen J, Liang A

Clinical cases applicability: Mullerian anomalies, primary amenorrhea, recurrent pregnancy loss

Learning objectives:

1) Describe the embryologic origins of the reproductive tract

2) Identify genes and hormones involved in sexual differentiation

3) Understand the mechanisms of how Mullerian anomalies form

What are the embryologic origins of the reproductive system?

Mesoderm  Urogenital ridge

1) Genital ridge  undifferentiated gonad  ovary/testis

2) Nephrogenic cord  kidneys

3) Paramesonephric (Mullerian) ducts  fallopian tubes, uterus, upper vagina

4) Mesonephric (Wolffian) ducts  ureters, male genital ducts, seminal vesicles

How does sexual differentiation occur (see figure 1)?

SRY gene (Sex-determining Region of the Y chromosome) in the short arm of Y chromosome  encodes for SRY protein (previously known as testis-determining factor – TDF)

SRY protein  chain of events leading to gonad differentiation into testes and production of anti-mullerian hormone and testosterone

What are key hormones in fetal male development (see figure 1)?

– Testosterone  persistence and differentiation of wolffian (mesonephric) ducts

– Anti-mullerian hormone (produced by Sertoli cells) regression of mullerian ducts

What are conditions required for normal fetal female development (see figure 1)?

– Considered the “default”

– Absence of SRY, testosterone & Anti-mullerian hormone  regression of wolffian ducts and persistence of mullerian (paramesonephric) ducts

What causes mullerian anomalies (see figure 2)? Affects 2-4% in women with normal reproductive outcomes, 5-25% for women with adverse reproductive outcomes; NORMAL ovarian function with normal secondary sex characteristics

1) Errors in organogenesis – Mullerian agenesis (“MRKH” Mayer Rokitansky Küster Hauser), all or part of the mullerian tract fails to form or is underdeveloped: absent vagina, variable uterine development

2) Errors in fusion

a. Uterine didelphys – “double uterus”, two mullerian ducts fail to fuse, duplication of the reproductive structures

b. Bicornuate uterus – Fundus is indented, partial fusion of the mullerian ducts

c. Unicornuate uterus – asymmetric lateral fusion defect – one cavity usually normal, while other duct poorly developed (+/- rudimentary horn)

3) Errors in septal resorption

a. Septate uterus (complete or partial) – Normal external surface of the fundus (compared to bicornuate), incomplete resorption of the midline septum between the 2 mullerian ducts

b. Arcuate uterus – slight midline septum with minimal, and often broad, fundal cavity indentation

Why are mullerian anomalies associated renal anomalies? What is the incidence?

– Paramesonephric system develops with the renal system (both originate from the urogenital ridge)

– Renal anomalies are found in 20-30% of women with mullerian defects

Mullerian Anomalies

Jehnsen J, Liang A

Figure 1

Figure 2

References:

– Beckmann, Charles R. B. (Eds.) (2010) Obstetrics and gynecology.Baltimore, MD : Wolters Kluwer Health/Lippincott Williams & Wilkins

– DeCherney AH, Nathan L, Laufer N, Roman AS. CURRENT Diagnosis & Treatment: Obstetrics & Gynecology, 11e; 2013

– Renu D, Rao B G, Ranganath K, Namitha. Persistent mullerian duct syndrome. Indian J Radiol Imaging 2010;20:72-4

– Iverson RE, DeCherney, AH, Laufer, MR. Clinical manifestations and diagnosis of congenital anomalies of the uterus. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (2017)

00:03
we’ve been trying for about a year and
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friends dripped throughout that year it
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starts to get pregnant and and I think
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then a shadow of doubt started to creep
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in for both of us for both myself and my
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husband we started to wonder you know
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should something have happened for us it
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wasn’t so much a shock it was gradual it
00:20
happened you know every month my period
00:22
rotella I’d be here two days before it
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was gob feeling his dragging pains in my
00:25
stomach I just thought there would be
00:27
something simple and straightforward
00:28
that we’d overlooked and there wasn’t
00:31
and and they said we needed to see a
00:33
specialist which was very very scary and
00:35
I remember at that point I think this
00:38
was the first of my burst into tears and
00:40
doctors and waiting rooms the first of
00:42
many I have to say I think the shock of
00:44
it and also it felt very serious all of
00:47
a sudden and if we were seeing a
00:49
specialist a fertility specialist then
00:51
there was a problem with our fertility
00:53
complete kicking the team’s I think you
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know it said before it’s you’re born
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into thinking you know you’re in here on
01:00
this earth to do what you’re doing you
01:02
you have children and you pass on your
01:04
name you pass on your bloodline and all
01:08
that rubbish really but exist because
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it’s not have assist you but it might
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not happen because I think that’s the
01:14
one of the most difficult things about
01:16
it really you do feel that you are not
01:18
the same as everyone else that you’ve
01:19
kind of failed as a woman somehow
01:22
everyone else seems to be able to do
01:23
this thing so easily and you just grow
01:25
up expecting that you’ll be able to have
01:27
children if you want to and discovering
01:30
that you can’t it’s really hard to
01:33
describe how much that affects you
01:35
actually how much it affects the way you
01:36
see yourself and how you feel about
01:38
yourself and I realized as I sort of
01:42
went into it I had no idea what it
01:44
entailed at all and I think I think it’s
01:48
this thing that’s kind of thrown around
01:50
and people always just as soon as a as
01:52
an option and first of all they assume
01:55
that without any real understanding of
01:57
how often it doesn’t work you know for
02:00
one thing and just the physical and
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emotional toll it takes on you
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you