OBGYN - Infertility

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(Created page with ' Note that the testable material is in a doc on angel; this stuff from lecture is simply what she went over verbally. =Infertility= ==Causes and Diagnosis== ==Objectives== *…')
 
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Note that the testable material is in a doc on angel; this stuff from lecture is simply what she went over verbally.
 
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=Infertility=
=Infertility=
-
 
-
==Causes and Diagnosis==
 
==Objectives==
==Objectives==
-
*To become acquanted with:
+
*To become acquainted with:
-
**prevalence of infertility in the general population
+
**The prevalence of infertility in the general population
-
**the causes of female and male infertility
+
**The causes of female and male infertility
**A systematic approach to the evaluation of the infertile couple
**A systematic approach to the evaluation of the infertile couple
-
==Definition==
+
==Prevalence===
-
*Infertile is one year of unprotected sex without pregnancy.
+
*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.
*Women are most fertile 15-25 yo.
*The timing is important.
*The timing is important.
**Not so exquisite that you must be down to the minute.
**Not so exquisite that you must be down to the minute.
-
**Those expensive kits aren't worth it.
+
*Those expensive kits aren't worth it.
*Sperm will stick around a fair bit.
*Sperm will stick around a fair bit.
-
 
-
==Prevalence==
 
-
*20% of couples after 1 year of unprotected sex.
 
-
**Has stayed the same over many decades.
 
-
*Now, however, people don't get married because they have birth control and then get married later and have more trouble as 30 yos getting pregnant.
 
-
**33% of the female partner is over the age of 35.
 
-
*No appreciable change since the 1950s but more treatment are available.
 
==What does it take to get pregnant==
==What does it take to get pregnant==
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*Also requires proper coitus and high frequencey
*Also requires proper coitus and high frequencey
-
==Pathophys of Female Infertility==
 
-
===EStrogen Deficiency===
+
*Female components of fertility:
-
*Without estrogen (from the ovary, the follicle), they don't ovulate.
+
**Regular ovulation
-
*Check FSH levels:
+
**Patent fallopian tubes
-
**Low: that's why they aren't ovulating
+
**Receptive endometrium
-
**High: follicle is not responding
+
**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.
-
===FSH===
+
===Semen Analysis===
-
*This is themost reliable test to determine if the ovary is functioning.
+
*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.
-
===Polycystic ovaries===
 
-
*Hirsutism, diabetes, acanthosis nigricans, receading hair line.
 
-
*FSH levels are low, relative to the LH levels.
 
-
*Her granular cells are making testosterone.
 
-
*The follicles of PCOS are defuct.
 
-
===Lean Anovulation===
+
*Chemistries: FSH, testosterone, TSH, prolactin
-
*Kenyan Runner propably has mean PCOS.
+
-
**Measure both FSH and LH (2:1, 3:1, or 4:1)
+
-
*Functional chronic anovulation may occur in anorexic women or highly trained athletes.
+
-
===The normal menstrual cycle===
 
-
*Length of the post-ovulatory phase should average 14 days (at least 12).
 
-
*We don't want post-ovul to take place at the cost of the pre-ov phase.
 
-
*Short post-ov indicates a luteal phase defect.
 
-
*We use "ovulationn prediction kit" which measures urine LH.
 
-
===35 yo over achiever===
+
*Imaging:
-
*This is the usual suspect now-a-days.
+
**Vasogram
-
*Fertility declines after the age of 35.
+
**Sonogram of the scrotum and groin
-
*Eggs: 6 million in utero, 1 million at birth, ...
+
**CT or MRI of the sella turcica if prolactin is elevated
-
===Male Infertility===
 
-
*Azoosperm = no sperm at al.
 
-
*Oligo-asthenospermia = few sperm, don't work well.
 
-
**Associated with increased scrotal heat.
 
-
**Expsoure to meds / Radx.
 
-
**Congenital
 
-
*Erectile and ejaculatory dsyfunction
 
-
===Treatable Azoospermia===
+
*Testicular biopsy:
-
*Look for incomplete androgen sensitivity.
+
**Indicated for azoospermia or severe oligospermia with normal FSH and LH
-
*If biopsy shows sperm we can extract and use it for insemination.
+
-
**If not, get a donor.
+
-
===Menopause onset===
+
==Summary==
-
*Mother's age of menopause is a good predictor of when the pt will commence menopause.
+
*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

Current revision as of 18:30, 15 December 2011

Contents

[edit] Infertility

[edit] 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

[edit] 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.

[edit] 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.

[edit] 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

[edit] 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

[edit] 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

[edit] 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

[edit] 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.

[edit] 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.

[edit] 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

[edit] 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

[edit] 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.

[edit] 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.

[edit] 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


[edit] 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


[edit] 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

[edit] 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.

[edit] 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

[edit] Tubal Diseases

[edit] 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.

[edit] 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.

[edit] 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.

[edit] 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.

[edit] 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

[edit] 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)

[edit] Azoospermia

[edit] 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

[edit] 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

[edit] 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

[edit] 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

[edit] 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

[edit] Evaluation of Female Infertility

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

[edit] 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

[edit] 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

[edit] 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.

[edit] 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.

[edit] 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

[edit] 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

[edit] 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.

[edit] 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

[edit] 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

[edit] 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
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