InfertilityInfertility

Edward A. Rose, M.D., M.S.A.Edward A. Rose, M.D., M.S.A.

North Oakland Medical North Oakland Medical CentersCenters

Pontiac, MIPontiac, MI

Description of CaseDescription of Case

29 y o G29 y o G00 concerned about not concerned about not getting pregnantgetting pregnant

Unprotected sex X 1 ½ yearsUnprotected sex X 1 ½ years PMHx negativePMHx negative No other complaintsNo other complaints

Further History?Further History?

Frequency of intercourse, use of Frequency of intercourse, use of lubricants (e.g., K-Y gel) that could be lubricants (e.g., K-Y gel) that could be spermicidal, use of vaginal douches after spermicidal, use of vaginal douches after intercourse, or presence of any sexual intercourse, or presence of any sexual dysfunction such as anorgasmia or dysfunction such as anorgasmia or dyspareuniadyspareunia

Menstrual history, frequency, and Menstrual history, frequency, and patterns since menarche; weight patterns since menarche; weight changes, hirsutism, frontal balding, acnechanges, hirsutism, frontal balding, acne

History (continued)History (continued) Male partners: previous spermogram Male partners: previous spermogram

results, history of impotence, premature results, history of impotence, premature ejaculation, change in libido, history of ejaculation, change in libido, history of testicular trauma, previous relationships, testicular trauma, previous relationships, history of any previous pregnancy, history of any previous pregnancy, existence of offspring from previous existence of offspring from previous partnerspartners

History of sexually transmitted diseases; History of sexually transmitted diseases; surgical contraception (e.g. vasectomy, surgical contraception (e.g. vasectomy, tubal ligation); lifestyle; consumption of tubal ligation); lifestyle; consumption of alcohol, tobacco, and recreational drugs; alcohol, tobacco, and recreational drugs; occupation; physical activitiesoccupation; physical activities

History (continued)History (continued)

Either partner currently under Either partner currently under medical treatment, the reason, and medical treatment, the reason, and whether they have a history of whether they have a history of allergiesallergies

Complete review of systems may be Complete review of systems may be helpful to identify any helpful to identify any endocrinological or immunological endocrinological or immunological problemproblem

Your PatientYour Patient

History of weight gain, acne, facial History of weight gain, acne, facial hair, irregular menseshair, irregular menses

ROS + for an elevated glucose and ROS + for an elevated glucose and elevated BP a few months agoelevated BP a few months ago

Exam shows android body habitus, Exam shows android body habitus, weight 205#, acne on face and back, weight 205#, acne on face and back, some facial hairsome facial hair

Diagnosis, first years?Diagnosis, first years?

DefinitionDefinition

Inability to Inability to conceive after one conceive after one year of intercourse year of intercourse without without contraceptioncontraception

Counsel patience!Counsel patience!

Percent Who Conceive Within:

50%

22%

13%

5%

10%

3 Months

6 Months

12 Months

24 Months

Never

Causes of InfertilityCauses of Infertility

23%

18%

14%9%

5%

3%

28%

Male Factor

OvulatoryDysfunction

Tubal Damage

Endometriosis

Coital problems

Cervical factor

Unexplained

Male FactorMale Factor

Male partner should be evaluated Male partner should be evaluated simultaneously with female partnersimultaneously with female partner

Causes of male infertility:Causes of male infertility:– Reversible conditions (varicocele, obstructive Reversible conditions (varicocele, obstructive

azoospermia)azoospermia)– Not reversible, but viable sperm available Not reversible, but viable sperm available

(ejaculatory dysfunction, inoperative obstructive (ejaculatory dysfunction, inoperative obstructive azoospermia)azoospermia)

– Not reversible, no viable sperm (hypogonadism)Not reversible, no viable sperm (hypogonadism)– Genetic abnormalitiesGenetic abnormalities– Testicular or pituitary cancerTesticular or pituitary cancer

Ovulatory DysfunctionOvulatory Dysfunction

Causes 18% of infertilityCauses 18% of infertility Diagnosed byDiagnosed by

– Menstrual irregularitiesMenstrual irregularities– Basal body temperaturesBasal body temperatures– Ovulation prediction kitsOvulation prediction kits– Serum progesterone levels (18-24 days Serum progesterone levels (18-24 days

after onset of menses; level > 3 ng/ml is after onset of menses; level > 3 ng/ml is diagnostic of ovulation) diagnostic of ovulation)

BBT KitBBT Kit

Completed Sample BBT Completed Sample BBT ChartChart

Evaluation of Ovarian Evaluation of Ovarian ReserveReserve

Assessed in women > 35 or younger women Assessed in women > 35 or younger women with risk factors for premature ovarian failurewith risk factors for premature ovarian failure

Day 3 FSH and CCCT (clomiphene citrate Day 3 FSH and CCCT (clomiphene citrate challenge test)challenge test)– Administer 100 mg clomiphene on cycle days 5-9Administer 100 mg clomiphene on cycle days 5-9– Measure FSH on days 3 and 10; maybe estradiol Measure FSH on days 3 and 10; maybe estradiol

on day 3 (conflicting data)on day 3 (conflicting data)– Normal test not useful, but abnormal test virtually Normal test not useful, but abnormal test virtually

assures that pregnancy will not occur even with assures that pregnancy will not occur even with treatmenttreatment

Ultrasound may also be usedUltrasound may also be used

Causes of Ovulatory Causes of Ovulatory DysfunctionDysfunction

Polycystic ovary syndromePolycystic ovary syndrome Hypothalamic anovulationHypothalamic anovulation HyperprolactinemiaHyperprolactinemia Premature and age-related ovarian failurePremature and age-related ovarian failure Luteal phase defectLuteal phase defect

– Abnormalities of corpus luteum resulting in Abnormalities of corpus luteum resulting in inadequate production of progesteroneinadequate production of progesterone

– Based on finding of 2 consecutive endometrial Based on finding of 2 consecutive endometrial biopsy specimens showing histology > 2 days biopsy specimens showing histology > 2 days out-of-phase with actual biopsy dateout-of-phase with actual biopsy date

– Relevance is controversialRelevance is controversial

Polycystic Ovarian Polycystic Ovarian SyndromeSyndrome

Oligomenorrhea/amenorrhea and Oligomenorrhea/amenorrhea and hyperandrogenismhyperandrogenism

Prevalence: 5%Prevalence: 5% Among women with ovulatory dysfunction, Among women with ovulatory dysfunction,

70% have PCOS70% have PCOS Clinical evidence: hirsutism, acne, obesityClinical evidence: hirsutism, acne, obesity Lab evidence: elevated testosterone, Lab evidence: elevated testosterone,

elevated DHEA-Selevated DHEA-S ““Polycystic ovaries” supportive, not Polycystic ovaries” supportive, not

diagnosticdiagnostic

PCOS Treatment ApproachPCOS Treatment Approach

Weight loss if BMI > 30Weight loss if BMI > 30 Clomiphene to induce ovulationClomiphene to induce ovulation If DHEA-S > 2, clomiphene + If DHEA-S > 2, clomiphene +

glucocorticoid (dexamethasone)glucocorticoid (dexamethasone) If clomiphene alone unsuccessful, try If clomiphene alone unsuccessful, try

metformin + clomiphenemetformin + clomiphene

Hypothalamic AnovulationHypothalamic Anovulation

Low levels of GnRH, low or normal Low levels of GnRH, low or normal levels of FSH/LH, low levels of levels of FSH/LH, low levels of endogenous estrogenendogenous estrogen

Associated factors: low BMI (< 20), Associated factors: low BMI (< 20), high-intensity exercise, extreme high-intensity exercise, extreme diets, stressdiets, stress

Treatment: lifestyle modificationTreatment: lifestyle modification

HyperprolactinemiaHyperprolactinemia

Causes: pituitary adenoma, psych medsCauses: pituitary adenoma, psych meds Test for pregnancy, thyroid diseaseTest for pregnancy, thyroid disease Imaging: MRI for macro vs. Imaging: MRI for macro vs.

microadenomamicroadenoma Treatment: Bromocriptine (dopamine Treatment: Bromocriptine (dopamine

agonist)agonist) After treatment, 80% of women will After treatment, 80% of women will

ovulate, 80% will get pregnantovulate, 80% will get pregnant Discontinue treatment once pregnancy Discontinue treatment once pregnancy

establishedestablished

What Can I Do?What Can I Do?

History and Physical - History and Physical - FemaleFemale

HistoryHistory– Menarche, pubertyMenarche, puberty– Menstrual historyMenstrual history– Pregnancies, abortions, Pregnancies, abortions,

birth controlbirth control– Dyspareunia, Dyspareunia,

dysmenorrheadysmenorrhea– STDs, abdominal STDs, abdominal

surgery, galactorrheasurgery, galactorrhea– Weight loss/gainWeight loss/gain– Stress, exercise, drugs, Stress, exercise, drugs,

alcohol, psychologicalalcohol, psychological

PhysicalPhysical– Weight/BMIWeight/BMI– ThyroidThyroid– Skin (striae, Skin (striae,

acanthosis acanthosis nigricans)nigricans)

– Pelvic (vaginal Pelvic (vaginal mucosa, masses, mucosa, masses, pain)pain)

– Rectal (uterosacral Rectal (uterosacral nodularity)nodularity)

History and Physical - MaleHistory and Physical - Male

HistoryHistory– Prior fertilityPrior fertility– MedicationsMedications– History of diabetes, History of diabetes,

mumps, undescended mumps, undescended testestestes

– Genital surgery, Genital surgery, trauma, infectionstrauma, infections

– EDED– Drug/alcohol use, stressDrug/alcohol use, stress– Underwear, hot tubs, Underwear, hot tubs,

frequent coitusfrequent coitus

PhysicalPhysical– Habitus, Habitus,

gynecomastiagynecomastia– Sexual Sexual

developmentdevelopment– Testicular volume Testicular volume

(5x3 cm)(5x3 cm)– Epididymis, vas, Epididymis, vas,

prostate by prostate by palpationpalpation

– Check for varicoceleCheck for varicocele

How Long To Wait Before How Long To Wait Before Work-upWork-up

For young patients, wait a yearFor young patients, wait a year Don’t wait a year if:Don’t wait a year if:

– Irregular menses; intermenstrual bleedingIrregular menses; intermenstrual bleeding– History of PIDHistory of PID– History of appendicitis with ruptureHistory of appendicitis with rupture– History of abdominal surgeryHistory of abdominal surgery– DyspareuniaDyspareunia– Age > 35Age > 35– Male factorsMale factors

On The First VisitOn The First Visit

Semen analysis Semen analysis Confirm ovulationConfirm ovulation

– Basal body temperatureBasal body temperaturechartingcharting

– Ovulation predictor kitsOvulation predictor kits(detect LH surge)(detect LH surge)

– Consider serum progesterone on day 21Consider serum progesterone on day 21

Labs: Labs: – TSH and prolactinTSH and prolactin– DHEA-S if concern for PCOSDHEA-S if concern for PCOS– FSH and estradiol on cycle day 3 and 10 if >35yFSH and estradiol on cycle day 3 and 10 if >35y– Cervical cultures prnCervical cultures prn

Three Months LaterThree Months Later

HysterosalpingogramHysterosalpingogram– Evaluates tubal patency and uterine Evaluates tubal patency and uterine

cavity shapecavity shape– Noninvasive but involves a tenaculumNoninvasive but involves a tenaculum– NotNot a painless test a painless test– Performed by radiology with gynecology Performed by radiology with gynecology

supervisionsupervision– Diagnostic and therapeuticDiagnostic and therapeutic

HysterosalpingogramHysterosalpingogram

Limited Clinical UtilityLimited Clinical Utility Postcoital testPostcoital test

– Limited diagnostic potential, poor predictive valueLimited diagnostic potential, poor predictive value Endometrial biopsy (luteal phase defect)Endometrial biopsy (luteal phase defect) BBTsBBTs

– Very inexpensive but interpretation difficultVery inexpensive but interpretation difficult– Temperature changes too late to be useful for timing Temperature changes too late to be useful for timing

intercourseintercourse Zona-free hamster oocyte penetration testZona-free hamster oocyte penetration test

– Not sure if hamster oocytes predict human oocytesNot sure if hamster oocytes predict human oocytes Immune testing for antiphospholipid, antisperm, Immune testing for antiphospholipid, antisperm,

antinuclear, antithyroid antibodiesantinuclear, antithyroid antibodies Routine cervical culturesRoutine cervical cultures

– Mycoplasma hominisMycoplasma hominis or or Ureaplasma urealyticumUreaplasma urealyticum KaryotypeKaryotype

Clomiphene CitrateClomiphene Citrate

Effective for anovulatory patientsEffective for anovulatory patients– Also used in unexplained fertility, but no Also used in unexplained fertility, but no

data to supportdata to support– Most effective for women with normal FSH Most effective for women with normal FSH

and estrogen, least effective in and estrogen, least effective in hypothalamic amenorrhea or elevated FSHhypothalamic amenorrhea or elevated FSH

Induces ovulation by unknown mechanismInduces ovulation by unknown mechanism Most pregnancies occur in first 3 cyclesMost pregnancies occur in first 3 cycles 80% will ovulate, 40% will become pregnant in 80% will ovulate, 40% will become pregnant in

3 cycles3 cycles

Clomiphene - ComplicationsClomiphene - Complications

7% twin gestations, 0.3% triplet 7% twin gestations, 0.3% triplet gestationsgestations

Miscarriage rate = 15%Miscarriage rate = 15% Birth defect rate unchanged from controlsBirth defect rate unchanged from controls Side effects: hot flashes, adnexal Side effects: hot flashes, adnexal

tenderness, nausea, headache, blurry tenderness, nausea, headache, blurry visionvision

Contraindications: pregnancy, ovarian Contraindications: pregnancy, ovarian cystscysts

Clomiphene - AdministrationClomiphene - Administration

50 mg daily, cycle day 3 through 750 mg daily, cycle day 3 through 7– Induce bleeding first with progesterone Induce bleeding first with progesterone

if amenorrheicif amenorrheic Intercourse QOD cycle days 12 - 17Intercourse QOD cycle days 12 - 17 Track ovulation with BBT or ovulation Track ovulation with BBT or ovulation

detection kitsdetection kits Increase dose to 100 mg daily, then Increase dose to 100 mg daily, then

150, if no ovulation occurs150, if no ovulation occurs

Thank You!Thank You!