Pocket Obstetrics and Gynecology

INFERTILITY

INFERTILITY EVALUATION

Definitions and Epidemiology (Fertil Steril 2008;90:S60)

• Infertility: No Preg after 1 y of regular unprotected intercourse. Consider eval & rx for woman >35 yo after 6 mo. Affects 7–8% of US women (Fertil Steril 2006;86:516). ↑ w/ age;  >40 yo → greatest infertility.

• Fecundity: Probability that a single menstrual cycle results in live birth

History (Fertil Steril 2004;82:S169)

• Gravidity, parity, Preg outcomes/assoc complications

• Age at menarche, cycle length & characteristics, dysmenorrheal moliminal sx

• Methods of contraception used in the past; frequency & timing of intercourse

• Duration of infertility & results of any prev eval & rx

• H/o thyroid dz, pelvic or abdominal pain, galactorrhea, hirsutism, dyspareunia

• Full medical & surgical Hx, including STIs & PID, prior abd/pelvic Surg

• Prev abn pap smears & any subseq rx

• Current meds including supplements & allergies

• Social history (SHx). Occupation, tobacco, EtOH, drug use

• Family history (FHx) of birth defects, mental retardation, or infertility

• Partner’s reproductive Hx (conceptions/children in other pairings, testicular trauma, chronic medical conditions, & meds). Remember male factor on diff dx.

Physical Examination

• Weight & BMI. Thyroid enlargement, nodule, or tenderness. Breast exam. Signs of androgen excess or acanthosis nigricans. Pelvic or abdominal tenderness, masses. Vaginal or cervical abnormality, secretions, or discharge. Uterine size, shape, position, & mobility. Adnexal mass or tenderness. Cul-de-sac mass, tenderness, nodularity.

Diagnostic Evaluation

• Ovulatory fxn: Oligomenorrhea (>35 d btw menses) or amenorrhea (>3 mo btw menses) → no further w/u. Luteal phase (cycle day 21 or 7 d after ovulation) serum prog >6 ng/mL confirms ovulation. Urinary LH (commercial ovulation predictor kits) generally reliable & correlate w/ serum LH. Serum FSH/LH ratio & estradiol (cycle day 3) or AMH (any time in cycle) indicate ovarian reserve. If ovulatory dysfxn → TSH, prolactin, & FSH for etiology.

• Anatomy assessment: HSG evaluates tubal patency & uterine cavity, endometrial polyps, submucosal fibroids. Schedule 2–5 d after last menses. Rx doxycycline 100 mg PO BID for 5 d if h/o PID or dilated tubes (Obstet Gynecol2009;113(5):1180). Beware HSG contrast can → tubal spasm (false + tubal blockage). TVUS shows uterine cavity contours & small intrauterine lesions. Sonohysterography(saline infusion sonogram) more accurate than HSG, as accurate as hysteroscopy for cavity assessment. 2D & 3D TVUS more sensitive than HSG for fibroids & polyps. Hysteroscopy for definitive dx + rx of cavity pathology. Laparoscopy definitive for tubal & pelvic pathology. Chromopertubation (the injection of indigo carmine dye through cervical canula w/ direct intra-abdominal observation of tubal spill for eval of tubal occlusion) & rx of mild dz (fimbrial agglutination, adhesion, endometriosis).

• See also male factor w/u & other diagnoses, below

PREMATURE OVARIAN INSUFFICIENCY (POI)

Definition & Epidemiology (Obstet Gynecol 2009;113:1355; Lancet 2010;376:911)

• Decline in nml ovarian fxn in a woman <40 yo. A form of hypergonadotropic hypogonadism. 0.3% of reproductive age ; 5–10%  w/ secondary amenorrhea.

Etiology

• Accelerated follicular atresia due to genetic syn (Turner XO → oocyte apoptosis; fragile X premutation → oocyte toxic prot). Autoimmune ovarian failure secondary to systemic autoimmune dz (check for type 1 DM, thyroiditis, hypoadrenalism). Ovarian toxins (chemo w/ alkylating agents, XRT, smoking, infxn such as mumps or CMV).

• Abn follicular stimulation due to defects in steroidogenic enzymes or defects in ovarian gonadotropin receptors (eg, FSH receptor mut)

• Result is ↓ ovarian estrogen production → ↓ negative feedback on pituitary → ↑ FSH, LH

Clinical Manifestations

• Primary or secondary infertility. Irreg menses vs. primary or secondary amenorrhea

• W/ fragile X – mental retardation, ataxia, premature ovarian failure

• W/ Turner syn – short stature, shield chest, web neck, low hairline, low set ears, aortic coarct, streak ovaries

• ↓ estrogen w/ primary infertility → impaired secondary sexual dev, dyspareunia (secondary to vaginal dryness), decreased bone density

• ↓ estrogen & secondary infertility → hot flashes, night sweats, emotional lability, dyspareunia, decreased bone density

Initial Workup

• ↓ estrogen → ↑ FSH, ↑ LH. POI if:

FSH >10 mIU/mL (except during the midcycle preovulatory LH surge)

FSH > LH w/ E2 <50 pg/mL (× 2 if ↑ FSH) = absent/nonfunctioning follicles

• Clomiphene citrate challenge test – check FSH on cycle day 3 & 10 after 100-mg clomiphene PO daily on cycle day 5–9; ↑ FSH after clomid sugg low ovarian reserve

• AMH–secretion by small preantral & early antral follicle granulosa cells reflects size of primordial follicle pool, declines w/ age, undetectable at menopause. Early marker of ovarian reserve, & AMH level is not cycle dependent. AMH >1 ng/mL – adequate ovarian reserve.

• AFC by transvaginal US – high variability, useful if equivocal labs

Follow-up Studies

• Genetics. Karyotype (identify individuals w/ any form of gonadal dysgenesis characterized by an absent or abn X chromo & those w/ any portion of a Y chromo), genetic testing for FMR1 gene permutations

• Adrenal autoantibodies by immunofluorescence assay

• Anti-islet cell Ab (given association w/ type 1 DM)

• Serum TSH, thyroid-stimulating Ig, thyroid peroxidase antibodies

• Bone mineral density to detect osteopenia

Treatment and Medications

• HT to ↓ sx of estrogen deficiency & prevent bone loss

• Daily calcium (1200–1500 mg) + Vit D (600–800 IU) for bone health

• Exogenous androgen – unclear role in mgmt; no high-quality evid

• Clinician sensitivity, additional psychological support

• IVF using donor oocytes – controversial in women w/ Turner syn

POLYCYSTIC OVARIAN SYNDROME (PCOS)

Definition (Nat Rev Endocrinol 2011;74:219)

• A d/o of ovarian fxn characterized by anovulation, elevated androgen levels, & polycystic ovaries. A/w obesity & insulin resistance (metabolic syn). Different diagnostic criteria used:

1990 NIH – NICHD – hyperandrogenism or hyperandrogenemia, oligoanovulation, & exclusion of other endocrine disorders

2003 Rotterdam criteria – 2 of following 3: Clinical or biochemical hyperandrogenism, oligo- or anovulation, polycystic ovaries. Other endocrine disorders must be excluded.

2006 androgen excess – PCOS society – clinical or biochemical hyperandrogenism w/ oligo-/anovulation &/or polycystic ovaries

Epidemiology & Pathophysiology

• 6–10% of women, depending on diagnostic criteria. Uncertain etiology, but hyperandrogenism may cause ovulatory dysfxn & abn gonadotropin secretion.

• Androgen excess → follicular arrest & ↑ LH. Hyperinsulinemia may also → follicular arrest & phenotypic features.

• Presentation may include excess body or facial hair, frequent shaving/plucking, irreg menstruation, infertility, alopecia, acne, obesity, metabolic syn.

Physical Exam

• Assess weight & BMI, hair pattern/growth, thyroid, galactorrhea (prolactin-secreting tumor), acanthosis nigricans

• Deep voice, male pattern facial/body hair, clitoromegaly may suggest androgen-secreting tumor or congen adrenal hyperplasia

Diagnostic Workup

• Document oligo- or anovulation by Hx, serum progesterone, or urinary LH testing

• Labs: Consider testing for serum androgens esp if no clinical hyperandrogenism – or – if frank virilization. TSH, FSH, & prolactin if pt anovulatory. 75 g, 2-h oral gluc tol test for women w/ hyperandrogenism w/ anovulation + acanthosis nigricans +

Obesity (BMI > 30 kg/m2, or >25 in Asian pop) + FHx of T2DM or GDM (Fertil Steril 2012;97(1):28)

• TVUS ovaries: ≥12 follicles in each ovary measuring 2–9 mm in diameter, &/or ovarian volume >10 mL indicates polycystic ovaries

• Endometrial bx if long Hx of oligomenorrhea due to ↑ endometrial cancer

Treatment (Fertil Steril 2008;89:505)

• Exercise & weight loss improve ovulation rate – 1st-line rx

• In women not attempting Preg, low-dose combination OCP may ↓ hyperandrogenism & risk of endometrial cancer

• Clomiphene citrate 1st-line ovulation induction in women desiring Preg (see below)

• Limit to 6 ovulatory cycles before considering 2nd-line rx

• Ovulation induction w/ exogenous gonadotropins is 2nd-line therapy. IVF is 3rd-line therapy.

TUBAL FACTOR INFERTILITY

Definition & Epidemiology (Curr Opin Infect Dis. 2004;17(1):49;2005)

• Infertility caused by obliteration of the fallopian tube, usually by prior pelvic infxn. 20–30% of infertility may be tubal factor. Very common.

Etiology

• Obliteration of the fallopian tube or damage to fimbriae by infectious or inflamm process. Most cases caused by prev Hx of PID.

• Less common causes are inflammation related to endometriosis, inflamm bowel dz, & surgical adhesions

Clinical Manifestations

• Usually asymptomatic but may have dysmenorrhea & dyspareunia if endometriosis

• Hx of PID, ectopic Preg, or prior pelvic Surg

Diagnostic Workup/Studies

• HSG – diagnostic, but also may ↑ fertility

• Consider laparoscopy w/ chromopertubation if endometriosis suspected

• Chlamydia Ab testing may be helpful to screen pts at high risk for tubal factor infertility, but role of testing has not been clearly defined yet (Fertil Steril 1994;62:305)

Treatment and Medications (Fertil Steril 2012;97:539)

• Prox tubal obst → tubal cannulation

• Mild hydrosalpinges → laparoscopic fimbrioplasty or neosalpingostomy

• Irreparable hydrosalpinges → IVF. Salpingectomy or prox tubal occlusion improves IVF Preg rates.

• Decision to pursue Surg vs. IVF based on age of woman, number of children desired, extent of tubal dz

RECURRENT PREGNANCY LOSS (RPL)

Definition (N Engl J Med 2010;363:1740)

• 3 or more consecutive Preg losses before 20 w gest; some recommend w/u after 2 consecutive losses, esp if age >35 yo or pt requests

Epidemiology & Etiology

• 1% of all couples attempting Preg. Increases in women <18 yo & >35 yo.

• Most very early (<10 w) miscarriages due to aneuploidy

• Autoimmune dz, anatomic abnormalities, & thrombophilias may lead to vascular insufficiency for developing conceptus, leading to miscarriage

Evaluation

• Determine actual gestational age at time of miscarriage rather than time of onset of sx if poss

• Ask about Hx of thrombosis or prev fetal death; Hx of prev Preg w/ breech presentation, dysmenorrhea, or menorrhagia (may suggest uterine anomaly or fibroids); chronic medical conditions such as thyroid dz, diabetes, or autoimmune dz such as lupus; smoking, obesity, EtOH use, caffeine use

Diagnostic Workup (Int J Gynaecol Obstet 2002;78:179)

• Parental karyotype for balanced translocations. Aneuploid karyotype of prior loss fetuses makes other causes less likely.

• Antiphospholipid Ab syn w/u: Lupus anticoagulant (RVVT and hexagonal phospholipid, or aPTT with mixing studies), β2 glycoprotein Ab (IgM/IgG), anticardiolipin Ab (IgM/IgG). Need 2 positive tests 12 w apart to make dx.

• Consider thrombophilia w/u only if pt has a Hx of thromboembolism. Test for Factor V Leiden, prothrombin G20210A mut, prot C, prot S, antithrombin III deficiency.

• Evaluate uterine cavity using HSG, hysteroscopy, sonohysterography, or transvaginal US

• No dx is made in 50% of cases of recurrent Preg loss (Fertil Steril 2012)

Treatment (N Engl J Med 2010;363:1740)

• If positive antiphospholipid antibodies, heparin 5000 U subcut twice daily & low-dose ASA can ↓ miscarriage rates. Low-molecular-weight-heparin dose not established.

• If genetic abnormality such as balanced translocation present, up to 70% live birth w/o intervention, but may consider preimplantation genetic screening

• If uterine septum → hysteroscopic resxn. Repair of bicornuate or unicornuate uterus not necessary as obstetric outcome often good & repair has higher risk.

• No rx for women w/ thrombophilias thus far has been found beneficial

MÜLLERIAN ANOMALIES

Definitions and Epidemiology (Hum Reprod Update 2011;17:761)

• An anomaly of the uterus, tubes, or upper vagina due to failure of dev, fusion, or resorption of Müllerian structures

5–6% of women (arcuate uterus 3.9%, septate uterus 2.3%, bicornuate 0.4%, unicornuate 0.3%, didelphys 0.3%). ↑ to 8% w/ infertility. ↑ to 13% w/ recurrent miscarriage. ↑ to 25% w/ mixed infertility & recurrent miscarriage. Many also have a GU abnormality.

Etiology (Fritz MA, Speroff L. Clinical Gynecologic Endocrinology & Infertility. Philadelphia, PA: Lippincott Williams & Wilkins; 2011.)

• Sporadic: Multifactorial & polygenic. 46 XX (92%); sex chromo mosaicism (8%).

• Risk factors: Hypoxia during Preg, MTX, DES, thalidomide, radiation, viral infxn

• Vertical fusion failure (canalization) → urogenital sinus & Müllerian tubercle separate

• Lateral fusion failure (duplication) → failure to merge bilateral Müllerian ducts

• Dev of the uterus, fallopian tubes, & upper vagina:

2 Müllerian (paramesonephric) ducts form from celomic epithelium beside the wolffian (mesonephric) ducts. In the absence of the SRY gene on the Y chromo & subseq MIS or AMH, Müllerian ducts proliferate & grow caudally & medially extending from the vaginal plate of the urogenital sinus to beside the developing ovary. In absence of testosterone, wolffian ducts involute. Canalization of the ducts occurs w/ a cranial lumen opening into peritoneal cavity. The paired ducts fuse in the midline forming the body of the uterus & the unfused lateral arms form the fallopian tubes. Resorption of medial aspects.

• Dev of urogenital sinus forms lower vagina, bladder, urethra

Urogenital sinus develops from the ventral portion of the cloaca (terminal hindgut; confluence of the urethra, rectum, & vagina). The caudal aspect of the paramesonephric ducts fuses w/ the urogenital sinus to form the vaginal & cervix.

Figure 8.1 Types of congenital uterine anomalies

Clinical Manifestations (Curr Opin Obstet Gynecol 2010;22:381; Fertil Steril 2008;89:219)

• Most often asymptomatic w/ nml secondary sex characteristics

• Sx can include primary amenorrhea or changes in menstrual cycle (uterine or vaginal malformations); dysmenorrhea or cyclic acute ± chronic pelvic pain;

Abn vaginal bleeding; foul-smelling vaginal discharge (worse at the time of menses); difficulty inserting a tampon; pelvic mass (from hematometra/hematocolpos); dyspareunia; infertility; recurrent Preg loss (esp septate uterus)

• Preg complications (higher rates of SAB, preterm birth, fetal malpresentation, labor dystocia, PPROM, placental abruption of previa, IUGR, & increased c-section) (Am J Obstet Gynecol 2011;205:558)

Specific anomalies (Obstet Gynecol 2013;121:1134)

• Vaginal agenesis/MRKH syn

Müllerian agenesis of upper vagina, ± uterus/tubes → blind pouch vagina. Affects 1 in 4000–10000 women. Nml ovarian & sexual dev. ↑ urinary tract, skeletal, & anter abdominal wall anomalies.

• Vaginal atresia

15% are segmental. Nml uterus, cervix, upper vagina. Primary amenorrhea. Hematocolpos → cyclic pelvic pain. Ddx: Imperf hymen, transverse septum. Segmental has ≥1 cm btw the upper & lower vaginal tract.

• Transverse vaginal septum

Defect in resorption, affects 1/2100–1/72000 women. Presents like vaginal agenesis.

Preoperative dilation can thin the septum to improve mobilization of the vagina at repair

• Uterovaginal abnormalities (longitudinal vaginal septa)

Defect in resorption → Preg loss, preterm deliv, dyspareunia, dysmenorrhea. 20% w/ renal anomalies. Up to 50% w/ endometriosis.

• Uterine didelphys

Defect in lateral fusion w/ double uterus & cervix ± double vaginas → postmenarchal dysmenorrhea, abd pain, palpable abdominal mass. Linked w/ ipsilateral renal agenesis (OHVIRA/Herlyn–Werner–Wunderlich syn)

• Unicornuate uterus

Only 1 Müllerian duct formed, w/ absent/incomplete contralateral side. 5% of all uterine anomalies; 1/4020–1/5400 . 74% have rudimentary horn, generally not communicating w/ hemiuterus. 40% w/ renal anomalies. 15% w/ endometriosis. Rarely extrapelvic or absent ovaries. Ectopic Preg can occur in uterine rudimentary horn; for rupture → prompt surgical mgmt ± MTX. Recommend removal of rudimentary horns prior to Preg. Obstetric & infertility complications: Late 1st & early 2nd trimester SAB (25%), decreased fecundity, preterm deliv (20%), 3rd trimester fetal demise (10%), placenta accreta, postpartum atony.

• Cervical atresia

4 categories: (1) Agenesis, (2) fragmentation, (3) fibrous cord, (4) obst. 50% also w/ vaginal agenesis. 33% w/ uterine anomalies. ↑ endometriosis, hematosalpinx, & pelvic adhesive dz. Rx unclear given very rare condition.

Diagnostic Workup/Studies (Fertil Steril 2008;89:219)

• Goal: Identify dilated/obstructed uterus &/or mass, pelvic anatomy, distance of an obstructed vagina from the perineum, thickness of a vaginal septum or atretic segment, & presence/absence of urinary tract anomalies

• Physical exam including pelvic ± rectal exam (adol/young adults). Exam under anesthesia ± vaginoscopy (pediatric pop).

• MRI is most sensitive imaging test for uterine anomalies & is preferred

• Pelvic US & HSG also imaging tools

• Vaginoscopy (gold std for vaginal or cervical anomalies)

• Laparoscopy (gold std for uterine anomalies)

• ± intraoperative HSG. ± karyotype.

Treatment and Medications (Fertil Steril 2008;89:1)

• Uterine/vaginal obst → immediately relieve obst (Surg)

If unable to proceed to OR immediately, place Foley catheter to avoid urinary retention. Consider percutaneous drainage, laparoscopic drainage, continuous OCPs to suppress endometrial growth until surgical repair.

• Vaginal anomaly → surgical or mechanical repair. If not emergent, medical/surgical intervention when emotionally mature/reproductive age. Vaginal dilators are used post-op to prevent stenosis. Overall pts have a satisfactory sex life similar to the nml pop. Discuss Preg options, IVF, surrogacy. Pts need multidisciplinary support including mental health providers & social work.

Progressive perineal dilation: 1st-line therapy as surgical neovagina ↑ stenosis & multi reoperations. More successful if greater depth of vaginal dimple, increased frequency of dilation, & sexual intercourse.

Surgical mgmt:

Vecchietti procedure (abdominal or laparoscopic technique w/ gradual traction on the vaginal dimple) → creation of a neovagina in 6 mo for 90% of pts. Must use vaginal mold continuously for the 1st 3 mo post-op.

McIndoe neovagina (dissection btw the urethra & rectum) → place split-thickness skin graft

Davydov neovagina (abdominal or laparoscopic-assisted technique w/ dissection of rectovesical space, mobilization of the peritoneum, creation of vaginal fornices, & attachment of the peritoneum to the introitus)

Williams vulvovaginoplasty (uses a vulvar flap to make a vaginal tube). Dilation is needed for a long period. Abn angle of neovagina.

Rotational flaps (use pudendal thigh, gracilis myocutaneous, labia minora, & other fasciocutaneous reconstruction). Also can create vagina from bowel.

• Septum → hysteroscopic resxn of uterine or longitudinal vaginal septum. Low or midtransverse vaginal septum approached vaginally; high septum & segmental vaginal atresia combine vaginal & abdominal approach. Pull through vaginoplasty if small length of atretic segment. Skin flaps or bowel if segment btw upper & lower vagina is larger.

• Bicornuate uterus – Strassman metroplasty unifies the 2 cavities. Rarely performed given difficulty & risk of future uterine rupture in labor.

• Rudimentary horn, obstructed hemivaginas, etc. → laparoscopic resxn

• Cervical atresia → hysterotomy & uterovaginal anastamosis vs. hysterectomy

• Didelphys, bicornuate rarely require repair. Uterine septum outcomes improved w/ resxn if 1st trimester loss or desires IVF.

MALE FACTOR INFERTILITY

Definition and Epidemiology (Fertil Steril 2006;86:S202)

• Inability of a male to achieve a Preg w/ a fertile female

• 20% due to purely male factors. Additional 30–40% combined male & female factors.

• Risk factors: Occupational or environmental exposure to chemicals, radiation, or heat; Hx of varicocele, mumps, hernia repair, pituitary tumor, anabolic steroid use, testicular injury, impotence

Etiology

• Hypogonadotropic (secondary) hypogonadism – hypothalamic/pituitary dz. Congen eg, Kallmann syn (abn neuronal migration resulting in anosmia & hypothalamic hypogonadism). Tumors – macroadenoma, craniopharyngioma. Infiltrative dz – sarcoidosis, TB, hemochromatosis. Vascular – infarction, aneurysm. Drugs. Obesity.

• Hypergonadotropic (primary) hypogonadism – testicular failure. Congen eg, Klinefelter syn (XXY), cryptorchidism (failure of descent of testes during fetal dev). Varicocele – dilation of the pampiniform plexus of spermatic veins in scrotum (left more common than right). Acq – cancer, infxn (viral orchitis, mumps), drugs (alkylating chemotherapeutic agents, antiandrogen agents), torsion, radiation, smoking, hyperthermia, antisperm antibodies.

• Other: Posttesticular defects – Dz of epididymis or vas deferens (infxn, vasectomy, CF). Retrograde ejaculation. Idiopathic (40–50%).

Clinical Manifestations and Workup

• Assess Hx: Prior pregnancies fathered, coital frequency & timing, childhood illness (mumps orchitis), developmental/pubertal Hx, systemic medical illnesses, prior surgeries (hernia repair), environmental exposures (heat), meds, Hx of STIs, trauma to genitals, sexual dysfxn

• Physical exam: Assess secondary sexual characteristics: Body habitus, hair distribution, gynecomastia. Examine penis including location of urethral meatus. Palpate testes & estimate testicular volume w/ Prader orchidometer. Assess presence/consistency of vas deferens & epididymidis, presence of varicocele. Digital rectal exam to assess masses.

• Semen analysis: Collect after 2–3 d of abstinence; 2 samples 1 mo apart; see Table 8.3 for assessment & nml values, & also eval leukocyte count, microscopic debris/agglutination, immature germ cells

• After initial w/u: Uro consult if indicated. Additional semen studies (sperm autoantibodies, biochemistry, culture, sperm-cervical mucus interaction, sperm fxn tests [sperm analysis, acrosome rxn, zona-free hamster oocyte penetration test, human zona pellucida binding test, sperm chromatin & DNA assays]). Endocrine eval: Testosterone, LH, FSH, prolactin. Postejaculatory urinalysis in pt w/ low volume semen to rule out retrograde ejaculation. Transrectal & scrotal US to identify obst & nonpalpable varicocele. Genetic testing – CFTR gene (a/w congen absence of vas deferens), karyotype to detect chromosomal abnormalities (a/w impaired testicular fxn), PCR to detect Y chromo microdeletions (a/w isolated spermatogenic impairment).

Treatment and Medications

• Treat underlying etiology if known. Improve coital practice – intercourse q2d during most fertile interval (3 d prior to & including day of ovulation).

• Sperm aspiration for obstructive azoospermia – TESE or MESA followed by IVF w/ ICSI (see below)

• Use ARTs as described below, ICSI useful for male factor infertility (see below). May need to consider donor sperm.

OVULATION INDUCTION AND ASSISTED REPRODUCTION

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 oligo- or anovulation, also for unexplained fertility & age-related decline in fertility. 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 cycle. 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 unsuccessful. 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 dev. 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 administration. 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/ hCG. 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), & OHSS.

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

• Advantages: Most cost-effective intervention prior to proceeding w/ IVF. Disadvantages: Requires patency of at least 1 fallopian tube.

• Indications: Sexual dysfxn (coitus can be avoided), cervical factor infertility, male factor infertility, unexplained fertility, endometriosis. Contraindications: Preg, bilateral fallopian tube occlusion, active pelvic infxn.

• Procedure: Wash ejaculated semen specimen to remove prostaglandins. Concentrate sperm in culture media. 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 success. 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 infxn.

• Procedure: Controlled ovarian hyperstimulation as above → follicle aspiration – usually transvaginally under US guidance, may also be done laparoscopically. 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 oocyte. 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 IVF.

• 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 cycle. 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 radiation. 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 Steril2010;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, misdiagnosis. 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 space. 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 levels. 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 progression. 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 & BP. 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: Low-dose 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 goal. 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.