Pocket ObGyn – Ovulation Induction and Assissted Reproduction
See Abbreviations

Definition

• Use of medication to stimulate nml ovulation in pts w/ oligo/anovulation

Clomiphene Citrate (Clomid) (Fertil Steril 2004;82:90)

• Indications: Initial rx of oligoor anovulation, also for unexplained fertility & agerelated decline in Contraindication: Preg.
• Mech of action: Estrogen agonist/antag – antag properties predominate, competitively binds estrogen receptors in hypothalamus ® ­ GnRH by hypothalamus ® ­ FSH, LH by pituitary ® follicular growth & ovulation
• Administer 50–150 mg PO daily for 5 d, starting cycle day 2–5 of menstrual Combined w/ timed intercourse or intrauterine insemination. Monit for ovulation using BBT, urine LH, elevated progesterone in midluteal phase, or US demonstrating preovulatory follicle prior to ovulation & subseq follicular collapse.
• Success rate for ovulation 80% – absence of ovulation or no Preg w/ known ovulation over 6 mo indicates failure of rx; many pts go to IVF if clomiphene citrate Addition of metformin may improve live birth rate (Fertil Steril 2010;94:2659).

Gonadotropin Injection (Fertil Steril 2008;90:S13)

• Many protocols based on nml physiology of menstrual cycle
• Mech of action: FSH stimulates granulosa cell proliferation & follicle LH stimulates theca cell production of androgen (converted to estrogen by granulosa cells). hCG stimulates follicular maturation of oocyte from prophase I through metaphase II & ovulation; may be used as alternative to LH for stimulation of ovulation.
• Typical administration: Gonadotropins (hMG or FSH) administered SQ or IM shortly after menstruation (~day 3 of cycle) ® hCG, LH, or GnRH agonist once follicle growth reaches target size (18–20 mm). Timed intercourse, intrauterine insemination or oocyte retrieval typically 34–36 h following hCG Progesterone or hCG for corpus luteum support following conception.
• Monitoring: Transvaginal US to assess follicular dev (diameter > 18 mm) & endometrial thickness prior to stimulation of ovulation w/ Estradiol level correlates w/ follicular maturation (E2 > 200 pg/mL per follicle). Progesterone level prior to hCG administration to determine premature LH surge.
• Complications of gonadotropins include multi gest (­ w/ lower mat age & higher number of embryos transferred), &

Intrauterine Insemination (IUI) (Cochrane Database Syst Rev 2012;4:CD003357)

• Advantages: Most cost-effective intervention prior to proceeding w/ Disadvantages: Requires patency of at least 1 fallopian tube.
• Indications: Sexual dysfxn (coitus can be avoided), cervical factor infertility, male factor infertility, unexplained fertility, Contraindications: Preg, bilateral fallopian tube occlusion, active pelvic infxn.
• Procedure: Wash ejaculated semen specimen to remove prostaglandins. Concentrate sperm in culture Inject sperm suspension directly into upper uterine cavity using a small catheter threaded through the cervix – timed to occur just prior to ovulation (check urine LH).
• Cumulative Preg rate of 5–20%, may attempt 3–6 cycles before proceeding w/ IVF

In Vitro Fertilization (IVF) (Cochrane Database Syst Rev 2012;18:CD003357)

• Advantages: Highest chance of Disadvantages: Expensive, higher risks of multi gest & OHSS given use of gonadotropins.
• Indications: Tubal factor infertility, failure of less invasive therapies, male factor infertility, diminished ovarian reserve, ovarian failure (egg donor use), uterine factor infertility (surrogacy). Contraindications: Mat dz in which Preg contraindicated (eg, malig), active pelvic
• Procedure: Controlled ovarian hyperstimulation as above ® follicle aspiration – usually transvaginally under US guidance, may also be done Oocytes mixed w/ prepared sperm in vitro, fertilization occurs w/i next 18 h. Embryo(s) transferred into uterine cavity on cycle day 3–5. Preg test (serum hCG) 10–12 d following xfer.
• Live birth rate of 45% – decreases w/ advancing mat age

Intracytoplasmic Sperm Injection (ICSI) (Fertil Steril 2008;90:S187)

• Advantages: Assists fertilization process by direct injection of sperm into Disadvantages: Technically demanding, high cost.
• Indications: Male factor infertility, select rare types of female infertility (morphologic anomalies of oocytes or zona pellucida inhibiting nml fertilization process). Contraindications: Same as for
• Procedure: Controlled ovarian hyperstimulation & follicular aspiration as outlined above
• Direct injection of single spermatozoon into cytoplasm of human oocyte
• Live birth rate of 30%

Fertility Preservation

Epidemiology (Semin Reprod Med 2011;29(2):147)

• The probability of a cancer dx in a premenopausal female is 11%
• Survival for many types of childhood malignancies is >80%
• Rx for many of these cancers can lead to infertility, so consideration of future reproductive desires important before Surg, chemo, or XRT

Pathophysiology

• Primary oocytes are arrested in prophase of the 1st meiotic division at birth
• Continuous apoptosis depletes the pool of primary follicles
• Alkylating chemo agents affect resting follicles & carry a high risk of ovarian failure
• Antimetabolites affect only metabolically active oocytes & granulosa cells, leading to a lower risk of ovarian failure
• Radiation also affects developing oocytes; dose of 24 Gy ® ovarian failure
• Intensive multiagent chemo & total body irradiation needed for bone marrow stemcell xplant results in >90% risk of permanent ovarian failure

Approaches

• Nonsurgical: Sperm cryopreservation or embryo cryopreservation are established methods for fertility preservation (Fertil Steril 2005;83:1622). Experimental techniques: If embryo cryopreservation is not poss due to lack of partner or desire to avoid creation of surplus embryos, some centers are capable of oocyte cryopreservation after a COH Some centers perform cryopreservation & in vitro maturation of oocytes from nonstimulated ovaries if a COH cycle is not poss.
• Surgical: Ovarian transposition Surg can be used to move an ovary out of the pelvis or abd if a pt is to undergo Ovarian tissue cryopreservation is a still experimental procedure where ovarian tissue is harvested, frozen, then thawed & retransplanted or individual follicles are isolated & grown in vitro. Cortical strips can be either transplanted back into pelvis or to abd or forearm. Fxn has been reported up to 7 y from transplantation (Fertil Steril 2010;93(3):762).
• Fertility preserving surgeries for gynecologic malignancies:

Cervical cancer ® trachelectomy in pts w/ tumor <2 cm in size & w/o lymph node metastasis; cerclage must be placed at time of Surg. Higher risk of 2nd trimester loss & preterm deliv.

Endometrial cancer ® progest therapy if well-differentiated tumor w/o lymph node involvement. Initial resp rate >60% in selected pts. Definitive therapy w/ hysterectomy should be performed as recurrence risk >50%.

Ovarian cancer ® unilateral salpingo-oophorectomy & lymph node dissection in malig germ cell tumor or early stage epithelial ovarian cancer

Preimplantation Genetic Testing

Definition (Fertil Steril 2008;90:S136)

• New technology for pts undergoing ART w/ goal of assessment for gene mut & aneuploidy prior to implantation to establish unaffected Preg
• PGD: Genetic testing of embryo when 1 or both of genetic parents are known to carry a specific gene mut or balanced chromosomal rearrangement
• PGS: Screening of embryo for aneuploidy in chromosomally nml couples

Indications

• Avoid Preg termination w/ fetus at risk for heritable debilitating dz, or medically indicated sex selection
• Reduce recurrent Preg loss in pts w/ known balanced chromosomal translocations

Procedure

• Small opening created in zona pellucida, cell or polar body extracted using small suction pipette, genetic analysis performed by PCR to assess gene defects, FISH for chromosomal anomalies
• 1st & 2nd polar bodies may be removed from oocytes after retrieval if genetic mother carrying detectable mut
• Blastomeres may be aspirated from embryo 3 d following fertilization

Counseling

• Embryo bx & culture may lower viability of Preg (NEJM 2007;357:9). Unanticipated birth of affected offspring – unprotected sex resulting in Preg, xfer of wrong embryo, Disposition of embryos found to have genetic anomalies & not used for xfer. False-positive results may result in discard of potentially nml embryos. Confirmatory prenatal testing after PGD recommended – CVS or amniocentesis.

Ovarian Hyperstimulation Syndrome (OHSS)

Definition and Epidemiology (Fertil Steril 2008;90:S188)

• Life-threatening complication of ovulation induction characterized by ovarian enlargement due to multi ovarian cysts & acute fluid shift out of intravascular Occurs in 0.2–6% ovulation induction cycles.
• Risk factors: Prior Hx of OHSS, age <35 y, low body weight, PCOS, higher doses of exogenous gonadotropins, high absolute or rapidly rising serum E2 Preg increases likelihood, duration, & severity of OHSS.

Pathophysiology

• Main trigger: hCG – physiologic or exogenous
• Ovarian enlargement due to stimulation by gonadotropins ® ­ ovarian hormones & vasoactive substances (cytokines, angiotensin,VEGF) ® ­ capillary permeability & acute 3rd space sequestration
• Massive extracellular exudative fluid accum & sev intravascular volume depletion & hemoconcentration ® multi organ system failure

Clinical Manifestations

• Signs/sx: Bloating, abdominal discomfort & distention, emesis, diarrhea, rapid weight gain, tense ascites, hemodynamic instability, respiratory difficulty (tachypnea), oliguria, HoTN, other signs of intravascular hypovolemia
• Lab findings: Hemoconcentration (­ Hct, leukocytosis, thrombocytosis), electrolyte imbalance (HoNa, hyperK, metabolic acidosis), ­ Cr, ­ liver enzymes
• Life-threatening complications: Acute renal failure, ARDS, heart failure, hemorrhage from ovarian rupture, thromboembolism

Treatment

• Self-limited: Rx mostly for symptomatic relief & stabilization
• Outpt mgmt for mild cases: Analgesia for pain, oral hydration, monitoring for Serial labs, serial US, daily weights. No intercourse, no strenuous activity to reduce risk of cyst rupture or ovarian torsion.
• Hospitalization & ICU care – supportive: Fluid mgmt – strict I&O, IV fluids (D5 NS MIVF 25% albumin prn) to maintain urine output & Thoracentesis, culdocentesis, & paracentesis under US guidance as needed. Ppx against thromboembolism – venous support stockings, pneumatic compression devices, prophylactic heparin or lovenox. ICU admission for mgmt of thromboembolic complications, pulm compromise, or renal failure. Cardiac: Invasive monitoring of CVP, PCWP. Pulm: Oxygen suppl, assisted ventilation, thoracentesis. Renal: Lowdose dopamine for renal compromise ® renal vessel dilation ® ­ renal bld flow. May require short-term dialysis.

Prevention (Fertil Steril 2010;94:389)

• Carefully monit after gonadotropins, esp for rapidly rising E2 levels, E2 >2500 pg/mL, or US evid of emergence of large number of intermediate-sized follicles (10–14 mm). Use minimum dose & duration of gonadotropin therapy necessary to achieve therapeutic Delay administration of hCG until estradiol levels plateau or ¯. Use GnRH agonist (eg, leuprolide) instead of hCG (can only be used in antag cycles). Use cabergoline (dopamine agonist) to reduce ovarian resp to FSH.

See Abbreviations