From Iusmicm

Contents 1 Infertility 1.1 Objectives 1.2 Prevalence= 1.3 What does it take to get pregnant 1.4 Components of Normal Fertility 1.5 Pathophysiology of Female Infertility 1.5.1 Ovulatory Dysfunction 1.5.2 Anovulation Associated with Ovarian Failure 1.5.3 Anovulation with Primary Gonadotropin Deficiency 1.5.4 Anovulation with Secondary Gonadotropin Deficiency 1.5.5 Functional Hypothalamic Amenorrhea 1.5.6 Polycystic Ovary Syndrome (PCOS) 1.5.6.1 PCOS and Physiology Review 1.5.6.2 PCOS Presentations: Obese and Lean 1.5.6.3 PCOS Endocrine Profile 1.5.6.4 PCOS Histopathology 1.5.6.5 Comparison of Function in Normal Ovaries vs PCOS 1.5.6.6 PCOS and Insulin Resistance 1.5.7 The Natural History of Oocyte Decline 1.5.8 Tubal Diseases 1.5.8.1 Tubal Disease: Endometriosis 1.5.8.2 Tubal Disease: Salpingitis 1.5.9 Endometrial and Uterine Disorders 1.5.10 Hostile Cervical Mucus 1.5.11 Chronic Cervicitis 1.6 Pathophysiology of Male Infertility 1.6.1 Azoospermia 1.6.1.1 Treatable Azoospermia 1.6.1.2 Untreatable Azoospermia 1.6.2 Oligo-asthenospermia 1.6.3 Erectile and Ejaculatory Dysfunction 1.7 Disorders of Coital Technique 1.8 Evaluation of Female Infertility 1.8.1 Confirmation of Ovulation 1.8.1.1 Confirmation of Tubal Patency 1.8.1.2 Confirmation of Post-coital Adequacy 1.8.1.3 Confirmation of Luteal Phase Adequacy 1.8.1.4 Diagnostics for Diminished Ovarian Reserve 1.8.2 Anovulation 1.9 Evaluation of Male Infertility 1.9.1 Semen Analysis 1.9.2 Evaluation in the presence of Abnormal Semen 1.10 Summary

Infertility

Objectives

• To become acquainted with:
  • The prevalence of infertility in the general population
  • The causes of female and male infertility
  • A systematic approach to the evaluation of the infertile couple

Prevalence=

• The definition of infertility is One year of regular unprotected intercourse without conception*
• The prevalence:
  • 20% of couples at the end of one year of exposure;
  • 15% at the end of two years of exposure
  • May be as high as 33% if the female partner is over the age of 35
  • Has not changed appreciably over the past 40 years
• Visits to the doctor’s office for infertility have increased as advanced treatments have become available

• Women are most fertile 15-25 yo.
• The timing is important.
  • Not so exquisite that you must be down to the minute.
• Those expensive kits aren't worth it.
• Sperm will stick around a fair bit.

What does it take to get pregnant

• Three ways to show that a woman can ovulate:
  • look at the corpus luteum via lapro
  • wash the egg out of the reproductive tract (don't do that anymore)
  • she gets pregnant
• Sperm have to be able to get to the ovum.

• And the people have to have sex.

• Much of infertility is and is not practical.
  • Wedge shaped pillows do not help.
  • Timing and intention are important: Intercourse 2-5 / week should give reasonable chances for getting pregnant.

Components of Normal Fertility

• Woman must ovulate (follicle erupting, corpus luteum, oocyte released), fillopian tube must be intact, egg must be competent enough to pass egg into fallopian tube, sperm must meet the egg.
• Million of sperm at the cervix, only about 1000 at the distal fallopian tube.
  • So we often try interuterine insemination to increase the numbers.
• Implantation requires that the endometrium have a nice mucus layer.
  • Requires cycling of estradiol from the corpus luteum.
  • Thick mucus is a good sperm trap.
  • Recall, however, tha the vagina is a sperm killer because of the pH being low.
• Also requires proper coitus and high frequencey

• Female components of fertility:
  • Regular ovulation
  • Patent fallopian tubes
  • Receptive endometrium
  • Favorable cervical mucus
• Male components of fertility:
  • Normal spermatogenesis
  • Erectile and ejaculatory competence (anterograde as opposed to retrograde ejaculation of sperm)
• Couple components of fertility:
  • Ideal coital frequency is between 2 and 5 times a week
  • Ejaculation should take place inside the vagina in close proximity to the cervix

Pathophysiology of Female Infertility

• Female infertility can arise from many causes:
  • Ovulatory dysfunction
  • Anovulation
  • Tubal disease
  • Abnormalities of the endometrium and uterine cavity
  • Cervical disorders

Ovulatory Dysfunction

• FSH levels are the most reliable test to determine if the ovary is functioning!

• Follicular Phase:
  • Short with inadequate follicular development or endometrial asynchrony
  • Long with the possibility of over-mature oocytes
  • Long follicular phase depicted

• Luteal Phase:
  • Short with normal peak progesterone
  • Normal with inadequate peak progesterone
  • Short luteal phase depicted

• Mid-luteal Progesterone:
  • Upper panel: normal with obvious pulsatility and peaks exceeding 16 ng/mL
  • Lower panel: luteal phase defect (LPD) with diminished pulsatility and peaks at 8 ng/mL or less
  • Note overlap between nadirs of normal pulses and peaks of LPD pulses

Anovulation Associated with Ovarian Failure

• Anovulation with ovarian failure menas that the ovary cannot respond to the pituitary's FSH.
  • FSH will be high.
  • Progesterone will not be made (because follicles are not generated / matured).

• There are many causes of ovarian failure:
• Turner syndrome
• 46XX Gonadal dysgenesis
• X chromosome rearrangements
• Chromosomal mosaicism
• True hermaphroditism
• Iatrogenic causes
  • Associated with chemotherapy or radiation for neoplasia

• Pregnancy may be possible with donated oocytes and in vitro fertilization if an intact uterus is present.
• All will have elevated follicle stimulating hormone (FSH)
  • Lack of breast development reflects the absence of ovarian function
  • Recall that breast development requires progesterone.

• Anatomic findings in ovarian failure include:
  • Small uterus
  • Fallopian tube remnants
  • Streak gonads

Anovulation with Primary Gonadotropin Deficiency

• Anovulation secondary to primary gonadotropin deficiency means the hypothalamus doesn't produce GnRH.
  • FSH values are low to undetectable
    • Recall that in ovarian failure, FSH is high as the pituitary is trying to stimulate the ovary but the ovary refuses.

• Primary gonadotropin deficiency can present in many ways, with pituitary-associated complications:
  • Isolated gonadotropin deficiency (only the gonadotropins are lost at the pituitary, not other hormones)
  • Gonadotropin deficiency with anosmia (loss of smell)
  • Panhypopituitarism (loss of all pituitary hormones)

• Clinical findings in primary gonadotropin deficiency:
  • FSH values are low to undetectable
  • Lack of breast development
    • Lack of breast development reflects the failure of the pituitary to stimulate the ovaries
    • Recall that breast development is secondary to FSH, so without pituitary stimulation of the ovary, the ovary makes no FSH and the breast don't develop.
    • Pectoral fat in obese patients may be falsely interpreted as breast development.
    • Note the immature nipple development depicted

• Patients with primary gonadotropin deficiency will ovulate with gonadotropin therapy.

Anovulation with Secondary Gonadotropin Deficiency

• Anovulation secondary to secondary gonadotropin deficiency means the pituitary doesn't produce LH or FSH.

• There are several causes of secondary gonadotropoin deficiency:
  • Prolactin secreting tumors:
    • Prolactin tumors may overwhelm the space of the pituitary and mechanically destroy / inhibit the gonadotropic cells.
    • Depicted above with double floor of sella turcica
  • Anorexia nervosa

• Note that even after refeeding, breast development is still immature.

Functional Hypothalamic Amenorrhea

• Functional hypothalamic amenorrhea is also called "Functional Chronic Anovulation" (FCA).
  • May be associated with emotional or physical stress
  • Common in situations where appearance and performance are linked

• Functional hypothalamic amenorrhea is probably a mild form of anorexia nervosa.

• Functional chronic anovulation findings:
  • Serum cortisol levels tend to be elevated
  • FSH and LH levels are both low
    • FSH is usually slightly higher than LH

Polycystic Ovary Syndrome (PCOS)

• Polycystic ovary syndrome occurs with defects in ciliary and ion channels.
• PCOS results in non-functional ovaries.
• The most common cause of anovulatory infertility

PCOS and Physiology Review

• Recall that the normal ovaries have thecal cells and granulosa cells.
  • The thecal cells make steroids--primarily testosterone.
  • The granulosa cells convert testosterone to estrogens--primarily estradiol (E2).
    • Granulosa cells use aromatase for this conversion.

PCOS Presentations: Obese and Lean

• PCOS often presents in a bimodal distribution over weight: either the obese case or the lean case.
• However, PCOS is associated with insulin resistance regardless of weight.
  • At least 50% of cases demonstrate insulin resistance.

• The classic presentation of PCOS is an obese case:
  • Obesity, hirsutism, oligomenorrhea
  • May also include acanthosis nigricans, receading hair line.
  • May present with acne in women with sparse body hair

• The atypical presentation of PCOS is in a lean case:
  • May be found in many lean women with anovulation
  • Some lean women have relatively normal menses but may develop amenorrhea with weight gain.
  • Marathon runners and other highly trained athletes often develop lean PCOS.

PCOS Endocrine Profile

• The PCOS pt will demonstrate:
  • High LH and Low FSH
    • LH-FSH ratio 2:1, 3:1, 4:1
  • High, normal, or elevated total testosterone
    • Elevated free testosterone
  • Low sex hormone binding globulin (SHBG)
  • Insulin abnormalities:
    • Recall that PCOS pts often have insulin resistance
    • Obese pts: elevated fasting insulin
    • Lean pts: elevated insulin in response to a glucose challenge

PCOS Histopathology

• Recall that normal oocytes are surrounded by cumulus and plump granulosa cells.
• Wedge resections reveal ovary with thickened capsule and dilated follicles
• Low power examination reveals dilated follicles without oocytes
• High power examination reveals thin granulosa layer

• We define a morphologic Criteria for PCOS as part of diagnosing:
  • Thickened ovarian capsule
  • Multiple cysts of varying size around the periphery of the ovary
    • Generally <10 mm mean diameter
  • Poorly developed granulosa layer

Comparison of Function in Normal Ovaries vs PCOS

• Normal ovaries:
  • LH stimulates steroidogenesis in the thecal cells.
  • FSH stimulates growth of follicles and increase in the number of granulosa cells.

• PCOS ovaries:
  • Recall that in PCOS, LH levels are high and FSH levels are low.
    • That is the LH-FSH ratio is 2:1 or 4:1, etc.
  • LH levels are sufficiently high for normal (or even excessive) thecal function: making testosterone.
  • FSH levels are low which leads to a poorly developed granulosa layer.
  • Aromatase levels (in granulosa cells) are low which leads to a poorly developed granulosa layer.
  • When the granulosa layer is poorly developed testosterone to estradiol conversion is deficieny.
  • When testosterone levels are high and poorly converted to FSH:
    • Oocyte demise occurs
    • Hirsutism occurs
    • Serum free testosterone levels rise

PCOS and Insulin Resistance

• Insulin stimulates inceased LH secretion by the pituitary.
  • Recall that LH stimulates testosterone synthesis by thecal cells.
  • Therefore, increased insulin means increased testosterone.
• Insulin blocks SHBG synthesis by the liver.
  • Recall that SHBG binds free testosterone in the serum to keep it from being active.
  • Therefore, increased insulin means increased freedom / activity of testosterone.

The Natural History of Oocyte Decline

• The number of oocytes in the ovary declines naturally and progressively through the process of atresia.
• Numbers of oocytes through the years:
  • 20 weeks gestation (in utero): 6-7 million oocytes
  • Birth: 1-2 million
  • Puberty: 300k-500k
  • 37 years: 25k
  • 51 years: 1k

• A steep decline in ovarian reserve begins naturally after age 35.
• Decline may be begin at an earlier age and become accelerated with exposure to chemotherapeutic agents or therapeutic radiation.
  • Even if menses return, oocyte quality may be affected.
  • Premature menopause is common when such treatments are initiated after age 30

Tubal Diseases

Tubal Disease: Endometriosis

• Tubal disease refers to lesions of the fallopian tubes that can result in female infertility.
• Tubal disease is described as minimal or advanced.

• Minimal tubal disease:
  • Minimal tubual disease may affect function without causing structural damage to the fallopian tubes.
  • Minimal tubal disease lesions range from reddish superficial blister-like implants to blue-black “powder burn” deep implants.
  • May interfere with normal fertilization and implantation.

• Advanced tubal disease:
  • Advanced tubal lesions may displace normal ovarian tissue.
  • Advanced tubal disease is characterized by chocolate cysts.
  • Adhesive disease interferes with normal oocyte pick-up.

Tubal Disease: Salpingitis

• Salpingitis is inflammation of the fallopian tubes
• There are two major pathogens that cause salpingitis: N. gonorrhea and Chlamydia trachomatis

• Salpingitis caused by N. gonorrhea:
  • Recall that N. gonorrhea is g-, diplo, maltose-, and not encapsulated (whereas N. meningitis is encapsulated)
  • N. gonorrhea salpingitis is usually symptomatic
  • N. gonorrhea causes intraluminal tubal disease and pelvic adhesions that arise from the purulent exudate

• Salpingitis caused by C. trachomatis
  • Recall that C. trachomatis is g- (too small), no shape (too small), obligate intracellular
  • C. trachomatis salpingitis is usually asymptomatic.
    • Asymptomatic state makes C. trachomatis a dangerous pathogen because non-detection lends itself to damage to the point of infertility.
  • C. trachomatis salpingitis damages by hypersensitivity response to the organism.

Endometrial and Uterine Disorders

• Endometrial and uterine disorders include hormonal issues, developmental issues, and mechanical aberations.

• Inadequate luteal phase leads to a delay in endometrial maturation
  • Inadequate luteal phase is thought to be the result of inadequate progesterone biosynthesis.
  • Endometrial biopsy / sectioning reveals absence of a pseudodecidual reaction below the endometrial surface.
  • Recall that the endometrium should generate a pseudodecidual reaction to become a good location for implantation.

• Intrauterine synechiae are intrauterine adhesions or connections.
  • Intrauterine synechiae are also called Asherman’s syndrome.
  • Scarring can lead to these connections.
  • Synechiae lead to obliteration of the uterine cavity or interference with normal placentation.

• Mullerian fusion anomalies can occur during gonadogenesis.
  • Gonadodevelopment / fusion issues are associated with preterm birth or recurrent miscarriages.
  • May be associated with incompetent cervix

• Mechanical endometrial / uterine disorders include Submucous leiomyomata and Endometrial polyps:
  • Both leiomyomata and polyps may prevent implantation through an IUD-like effect
  • Diagnosis of mechanical disorders is facilitated by hysterosalpingogram, saline infusion sonogram, and hysteroscopic view used for detection.

Hostile Cervical Mucus

• Good quality but poor sperm motility suggests the presence of sperm antibodies
• Scanty, clear, thick mucus suggests inadequate estrogen response
• Either condition may act as a barrier to sperm transport.

Chronic Cervicitis

• Any cervicitis should be treated
• Chlamydia is the most common cause of cervicitis
• Cervicitis presents as clear cervical mucus with varying locations of the transformation zone

Pathophysiology of Male Infertility

• Male infertility consists of:
  • Azoospermia (no sperm being made)
  • Oligo-asthenospermia (poorly functioning sperm)
  • Erectile and ejaculatory dysfunction (poor intra-vaginal delivery of sperm)

Azoospermia

Treatable Azoospermia

• Treatable azoospermia includes cases when spermatogenesis can be induced or sperm are recoverable.

• Azoospermia treated by induction:
  • Gonadotropin deficiency:
    • One form of gonadotropin deficiency is Kallman’s syndrome which is associated with mental retardation and anosmia.
  • Congenital absence of the vas deferens, as commonly seen in cystic fibrosis.

• Azoospermia treated by sperm recovery:
  • Deleterious Y chromosome microdeletions
  • Post-inflammatory obstruction of the epididymus or vas deferens
  • Post-pubertal radiation or chemotherapy, dose dependent

Untreatable Azoospermia

• Untreatable azoospermia occurs when spermatogenesis cannot be induced and / or sperm cannot be collected.
• Incomplete androgen insensitivity
• Sertoli cell only syndrome
• Klinefelter syndrome
  • Occasionally have sperm recoverable by biopsy
• Post inflammatory hyalinization of the germinal epithelium
  • Sequel of mumps
• Prepubertal radiation or chemotherapy

Oligo-asthenospermia

• Oligo-asthenospermia is having few, poorly functioning sperm.
  • Oligo-asthenospermia is associated with increased scrotal heat, expsoure to meds / Radx, and can also be congenital.
• Poorly functioning sperm can result from many abnormalities:
  • Varicocele
  • Testicular tumor
  • Testosterone deficiency
  • Substance abuse
• Chemical or radiation exposure

Erectile and Ejaculatory Dysfunction

• Erectile and ejaculatory dysfunction can be secondary to many disease states:
  • Diabetes
  • Hyperprolactinemia
  • Gonadotropin deficiency
  • Status post lymph node dissection
  • Spinal cord injury

Disorders of Coital Technique

• Some infertility issues have to do with intercourse (coitus) itself.

• Female coitus issues:
  • Vaginismus
  • Abnormalities of the hymen
  • Vaginal septa, transverse or longitudinal

• Male coitus issues:
  • Premature ejaculation: prior to intromission
  • Ejaculatory incompetence: failure to ejaculate after prolonged thrusting

• Couple coitus issues:
  • Oral or anal intercourse

Evaluation of Female Infertility

• To confirm infertility in a female pt, one must consider ovulation, mucus quality, tubal patency, and luteal phase dynamics.

Confirmation of Ovulation

• Cycle length:
  • Anything between 22 and 35 days is presumed to be normal
• Basal body temperature
  • Ovulation occurs at the lowest basal body temperature before a sustained rise
  • Only identifies ovulation after it has occurred because it reflects the postovulatory rise in progesterone
• Ovulation predictor kit:
  • Measures the preovulatory urine LH peak which generally occurs in the 24 hours prior to ovulation
  • Most accurate method other than serum LH

Confirmation of Tubal Patency

• Tubal patency studies should be done to be sure the tubes are open for oocyte transduction.
• The timing of patency studies is important: tubal patency studies should be perfomred after menses but before ovulation.
• There are several techniques for confirming patent fallopian tubes: hysterosalpingogram, hysteroscopy, laproscapy.
  • Hysterosalpingogram: dye contrast study of the uterus and fallopian tubes
  • Hysteroscopy: endoscopic study of the uterine cavity
  • Laparoscopy: endoscopic study of the abdomen and pelvis

Confirmation of Post-coital Adequacy

• We can test for appropriate spermatic movement and cervical mucus composition via the post-coital test.
• This test looks for motile sperm and watery mucus as desired results.
  • Furthermore, the mucus should spin a thread (Spinnbarkeit) and demonstrate arborization (ferning).
• Samples are aspirated from the endocervical canal 2-12 hours post-coitus.
  • Post-coital tests are done on post-coital materials that preceeds ovulation by 1-2 days.

Confirmation of Luteal Phase Adequacy

• Luteal phase adequacy tests look for proper endometrial changes (secretory) for implantation (secondary to corpus luteum / progesterone production).
• There are several luteal study techniques:
  • Serum progesterone levels can be checked to confirm the existence of the corpus luteum (the source of progesterone).
    • Progesterone tests should be done 7 days post-ovulation.
  • Endometrial biopsy can be performed to confirm secretory changes in the endometrium (the result of a proper luteal / progesterone phase).
    • Endometrial biopsy should be done 10-12 days post-ovulation.

Diagnostics for Diminished Ovarian Reserve

• Diminished ovarian reserve is the case of having low numbers of oocytes or impaired preantral oocyte development.
• Special tests for diminished ovarian reserve include:
  • Day 3 FSH and E2
    • FSH < 12, E2 <80
  • Clomiphene challenge test
    • FSH and E2 cycle day 3
    • Clomiphene 100mg day 5-9
    • FSH and E2 cycle day 10, 11, or 12
    • FSH <12, E2 >200
  • Anti-mullerian Hormone (AMH) assay
    • Level reflects ovarian reserve (follicles remaining)
    • Values < 0*75ng/ml predict poor response to multiple follicle recruitment desired for in vitro fertilization (IVF)
  • Antral Follicle Count
    • Less than 5 is a very poor prognostic sign

Anovulation

• When anovulation is suspected, the workup includes checking blood chemistries and anatomy.

• Chemistries checks:
  • LH, FSH
  • TSH
  • Prolactin
  • Testosterone, DHEA-S, 17 OH progesterone
  • Fasting glucose, insulin

• Imaging:
  • CT or MRI of the sella turcica
    • May reveal enlarged sella turcica reflecting an enlarged pituitary
  • Sonogram of the pelvis
    • May reveal string of pearls pattern typical of PCOS

Evaluation of Male Infertility

• Evaluation of male infertility includes inspection of semen and a physical examination
• Sperm count is not necessarily a good predictor of fertility.

Semen Analysis

• Semen analysis should occur after 3-5 days of abstinence.
• Normal seme characteristics include:
  • Volume: 2-5 cc
  • Count: 20 million / cc or 25 million total
  • Motility: 50-70% with rapid forward progression
  • Morphology: 30% normal forms using strict criteria

Evaluation in the presence of Abnormal Semen

• In the presence of amnormal semen, one should study chemistries, do imaging studies, and potentially perform a testicular biopsy.

• Chemistries: FSH, testosterone, TSH, prolactin

• Imaging:
  • Vasogram
  • Sonogram of the scrotum and groin
  • CT or MRI of the sella turcica if prolactin is elevated

• Testicular biopsy:
  • Indicated for azoospermia or severe oligospermia with normal FSH and LH

Summary

• Infertility may be the result of a single obvious factor in either partner or a combination of less obvious factors in both
• Because of the expense involved it is not practical to do every test on every couple
• A careful history and physical examination should be used to tailor the evaluation to the couple in question, keeping in mind the ages of the partners and the duration of infertility
• In older couples (female 35 or older), evaluation should be started after 6 months or less of infertility
  • Treatment should proceed in an orderly fashion with no more than 3 cycles of any therapy without moving on
  • IVF should be considered early