. ..

Infertility: 1 year of unprotected intercourse without pregnancy Primary infertility: no previous pregnancy has occurred Secondary infertility: infertility + prior pregnancy, although not necessary a live birth Fecundability is the probability of achieving pregnancy within a single menstrual cycle Fecundity is the probability of achieving a live birth within a single cycle Fecundability of the normal couple has 20-25% 90% of couples should conceive after 12 mo. Of unprotected intercouse

Cause of infertility

1.male factor 2.female factor 3.both female and male factor 4.unexplained infertility

25-40% 40-55% 10% 10%

Cause of female factor

1.ovulation dysfunction 2.tubal or peritoneal factor 3.unexplained infertility 4.miscellaneous causes

30-40% 30-40% 10-15% 10-15%

Diagnosis of anovulation

: irregular, unpredictable or infrequent menses When anovulation is suspected but uncertain -basal body temperature -progesterone measurement -urinary LH secretion

Basal body temperature

Measured each morning, on awakening and before arising Measured with an oral glass/mercury thermometer Test of ovulation: based on thermogenic property of progesterone Level of progesterone rise after ovulation so BBT increase BBT in follicular phase 97.0-98.0 F then higher in luteal phase (0.4-0.8F) and fall again to baseline just before or onset of mense Call Biphasic pattern : ovulation Thermogenic shift when progesterone > 5 ng/ml Most fertile interval is 2 day after thermogenic shift

progesterone measurement

Levels generally remain below 1 ng/ml during follicular phase Rise slightly on the day of LH surge 1-2 ng/ml Peak 7-8 day after ovulation then decline before mense Level > 3 ng/ml ovulation

urinary LH secretion

LH has short half life and rapid clear in urine Ovulation prediction kits or LH kits detect mid cycle LH surge in urine Test positive in single day, occasionally on 2 consecutive days Test must be done on daily, begin 2 or 3 days before surge Logically, first morning void : ideal specimen LH surge often begin in the early morning and are not detected in urine until several hr. later

urinary LH secretion cont.

Ovulation generally follow within 14-26 hr. after detection of urine LH surge and almost always within 48 hr. Interval of greatest fertility include the day of LH surge detection and following 2 days The day after the first positive test is the one best day for times intercourse and artificial insemination

Evaluation before induction of ovulation

anovulation thyroid disease, hyperprolactinemia, adrenal disease, pituitary or ovarian tumors, extremes of weight loss or exercise, polycystic ovary syndrome and obesity chronic anovulation risk endometrial hyperplasia and neoplasm endometrial sampling irregular mense

Classification of ovulation disorders

Group 1:hypothalamic-pituitary failure :hypothalamic amenorrhea stress, weight loss, exercise, anorexia nervosa and its variants, Kallmann syndrome and isolated gonadotropin deficiency hypothalamic or pituitary mass lesion Labs: low FSH and estrogen level normal prolactin concentration

Group 2:hypothalamic pituitary dysfunction amenorrhea or oligomenorrhea with or without associated hyperandrogenism PCOS with anovulation Labs:normal FSH, estrogen and prolactin concentration
Group 3:ovarian failure amenorrhea elevated serum FSH

Evaluation of other infertility factors

Before ovulation induction should screening semen analysis because infertility male factor 20-40% coexist preliminary evaluation with HSG or transvaginal ultrasonography when -history of previous pelvic infection or surgery, ectopic pregnancy, inflammatory bowel disease, pelvic pain or other symptom of endometriosis or an abnormal physical examination

Evaluation of other infertility factors cont.

older women : rapidly narrowing window of opportunity evaluate all relevant infertility factors before treatment induction ovulation exogenous gonadotropin should preliminary evaluation recommended : preliminary HSG and transvaginal ultrasonography when medical history or physical examination suspected coexisting uterine or tubal infertility factors, age over 35, and when ovulation induction required with exogenous gonadotropins

Evaluation of other infertility factors cont.

laparoscopy when abnormal HSG or signs and symptom of advanced pelvic disease

Induction of ovulation

Clomiphene citrate Exogenous gonadotropins Exogenous GnRH Dopamine agonists

Induction of ovulation with Clomiphene citrate

Clomiphene citrate first synthesized in 1956 approved for clinical use in United States in 1967 anovulatory women who recieve clomiphene citrate : -80% ovulation -50% of ovulated conceived

Pharmacology of Clomiphene

nonsteroidal triphenylethylene derivertive estrogen agonist and antagonist properties Main act purely as an antagonist or anti-estrogen weak estrogenic action metabolism 85% 1 2 different stereoisomers : 1.enclomiphene 2.zuclomiphene

Mechanism of action

compete estrogen nuclear estrogen receptor receptor receptor interfere receptor recycling hypothalamus: depletion estrogen receptor interpretation of estrogen level estrogen negative feedback GnRH secretion increase pituitary gonadotropin drive ovarian follicular development

Indications for Clomiphene treatment

traditional drug of choice for ovulation induction anovulatory infertile women evidence endogenous estrogen production 1. clinical oligomenorrhea, estrogen cervical mucus 2.serum estradiol determination (>40pg/ml) 3.normal menstrual response to progestational challenge hypogonadotropic hypogonadism clomiphene

Indications for Clomiphene treatment cont.

Luteal phase deficiency: clomiphene preovulatory follicular development Unexplained infertility infertility aggressive treatment Empiric clomiphene treatment intrauterine insemination

Clomiphene treatment regimen

Administer orally 3-5 progestin induced menses amenorrheic women start dose 50 mg tablet daily 5 50mg cycle ovulation dose 150 mg daily aggressive therapeutic alternation

Monitoring Clomiphene treatment

evaluate anovulation clomiphene induced ovulatory cycles anovulatory women LH surge 5-12 16-17 transvaginal ultrasound developing follicles presumptive evidence ovulation combined treatment with clomiphene and IUI transvaginal ultrasound : development of more than a single

Results of Clomiphene treatment

successfully induce ovulation in approximately 80% of properly selected women overall cycle fecundability is 15% anovulation ovulate clomiphene treatment Cumulative pregnancy rates of 70-75% can be expected over 6-9 cycles of treatment clomiphene induce ovulation 3-6 cycles ovulate infertility investigation exclude any other infertility factors

Results of Clomiphene treatment cont.

luteal phase deficiency luteal phase duration, serum progesterone concentration and cycle fecundability Empirical clomiphene treatment has relatively little benefit, yielding cycle fecundability 5 % and only one additional pregnancy for every 40 cycles Combined treatment with clomiphene and IUI achieves cycle fecundability between 8-10% and one additional pregnancy for every 15-20 treatment cycles

Side Effects of Clomiphene

Minor side effects are common transient hot flushes 10%,vasomotor symptoms, mood swing common, other mild or less common side effects include breast tenderness, pelvic pressure or pain, and nausea

Visual disturbance(blurred or double vision, scotomata, light sensitivity) are uncommon <2% but reversible

Peripheral Antiestrogenic effects of Clomiphene

peripheral sites in reproductive system : endocervix, endometrium, ovary, ovum and embryo Cervical mucus : cervical mucus production Endometrial growth and development : estrogen mediated endometrial growth minor effect or peak preovulatory endometrial thickness < 6mm tamoxifen or letrozole Ovary and embryo : embryo ovum

Risks of clomiphene treatment

multiple pregnancy :risk increased to 5-8 % congenital anomalies: no substantial evidence to increases miscarriage: no difference ovarian hyperstimulation syndrome transient abdominal discomfort, mild nausea, vomiting, diarrhea, and abdominal distention supportive breast and ovarian cancer: fertility drug nulliparous subfertile women incidence of borderline serous ovarian tumors but not with any invasive cancers

Treatment options after clomiphene failure

Clomiphene failure failure to ovulate in response to clomiphene treatment Many clomiphene resistant anovulatory infertile women response to alternative or combination treatment regimen

Options include 1.longer duration of clomiphene treatment, (7-10 days VS standard 5 days treatment regimen) 2.adjuvant treatment with glucocorticoids or exogenous human chorionic gonadotropin 3.preliminary suppressive therapy(oral contraception) 4.insulin sensitizing agent(metformin) 5.aromatase inhibitors(letrozole) 6.combination treatment 7.surgery ovarian wedge resection

Extended course clomiphene treatment

>50% response standard 5 day treatment regimen(150 mg daily) ovulate after longer duration of clomiphene treatment (7-10 days)

Clomiphene and glucocorticoids

induce ovulation fail to response to clomiphene alone most efficacious in women having elevated serum dehydroepiandrosterone sulfate (DHAS) concentration and also effective in those with normal DHAS and unselected populations of clomiphene resistant women Mechanism of glucocorticoid action remain unclear combined treatment 3-6 cycles

Clomiphene and hCG

Exogenous hCG LH surge IUI unexplained infertility and with coexisting male factor transvaginal ultrasound follicles mature for ovulation hCG follicles mature follicles induce atresia ovulation peak preovulatory follicular diameter in successful clomiphene induced ovulatory cycles ranges between 18-30 mm(mean 25 mm) Preovulatory follicle grows approximately 2 mm per day

Clomiphene and hCG cont.

Combined treatment with clomiphene and IUI LH surge insemination 1 detect ovulation generally occurs 14-26 hrs after urinary LH surge detection Exogenous hCG can be useful fail to detect the LH surge Ovulation occurs 34-46 hrs after hCG injection IUI usually performed approximate 36 hrs later

Preliminary suppressive therapy

Anovulation dysfunctional hypothalamic pituitary ovarian axis long used oral contraceptive empirically to suppress the often elevated androgen level clomiphene resistant anovulatory women ovulation rate excess 70% and cumulative pregnancy rate over 50%

Insulin sensitizing agents

Anovulation infertile women with PCOS and hyperinsulinemia clomiphene 5% ovulatory cycle screening for impaired glucose tolerance and diabetes PCOS insulin resistance insulin sensitizing agent Oral hypoglycemic drug DM insulin level

Insulin sensitizing agents cont.

metformin alone PCOS 4 metformin first line PCOS with anovulation adjuvant therapy clomiphene resistant anovulation Metformin is commonly associated with gastrointestinal side effects including nausea, vomiting, abdominal clamp, and diarrhea

Letozole

aromatase inhibitor may be another potential option for clomiphene resistant anovulatory women Mechanism of action: Blocking action of enzyme aromatase to convert testosterone and androstenedione to estrogen inhibit peripheral estrogen production and no direct peripheral antiestrogen effect

Laparoscopic ovarian drilling

The technique involve multifocal ovarian cautery, diathermy, or laser vaporization (approximate 10-20 sites per ovary) aimed to decreasing intraovarian and systemic androgen concentrations by ablating some of the hypertrophic stroma in polycystic ovaries ovarian drilling adhesion fertility function 40-90% of women have ovulated after laparoscopic ovarian drilling and at least half of those have conceived

Laparoscopic ovarian drilling cont.

clomiphene resistant : ovarian drilling clomiphene and exogenous gonadotropin treatment option in clomiphene resistant anovulatory infertile women

Induction of ovulation with Exogenous gonadotropins

Exogenous gonadotropin have been used for more than 40 years to induce ovulation in gonadotropin deficient women and those who fail to respond to other

Indications for exogenous gonadotropin treatment

1.hypogonadotropic hypogonadism 2.clomiphene resistant ovulation

3.unexplained infertility

hypogonadotropic hypogonadism

drug of choice is menotropins contain both FSH and LH LH is also required for normal steroidogenesis, luteinization, and ovulation insufficient luteal phase support :premenstrual spotting, grossly short luteal phase, and endogenous LH less than 3 IU/L luteal support : supplemental hCG(2,000-2,500 IU every 3-4 days) or progesterone

clomiphene resistant ovulation

exogenous gonadotropin is alternative choice Clomiphene resistant anovulatory women with PCOS Dose hypogonadotropic hypogonadism clomiphene resistant anovulatory women with polycystic ovary syndrome generally respond to relatively low doses of gonadotropin level luteal phase support in PCOS

unexplained infertility

increase cycle fecundity superovulation dose luteal phase support

Exogenous gonadotropin treatment regimen

1.Step-up regimen 2.Step-down regimen 3.Sequential treatment with clomiphene and gonadotropins 4.Adjavant treatment with GnRH agonists

5.Novel gonadotropin treatment regimens

1.Step-up regimen

Use in hypogonadotropic hypogonadism clomiphene resistant anovulation dose 75 IU daily effective dose 4-7 evaluate serum estradiol level with or without transvaginal sonography PCOS exogenous gonadotropin mornitor

1.Step-up regimen cont.

Ovarian hyperstimulation low slow treatment regimen gonadotropin stimulating span 7-12 PCOS low dose longer duration metformin gonadotropin improve response

2.Step-down regimen

high dose (150-225 IU daily) and decrease gradually regimen response threshold one or more previous stimulating cycles

3.Sequential treatment with clomiphene and gonadotropins

clomiphene resistant anovulation unexplained infertility benefit Typical cycle involves a standard course of clomiphene treatment (50-100 mg daily) followed by low dose FSH or hMG (75 IU daily) beginning on the last day of clomiphene therapy or the next day monitor standard gonadotropin stimulated cycles

4.Adjavant treatment with GnRH agonists

clomiphene resistant anovulation with PCOS : premature follicular luteinization during exogenous gonadotropin stimulation higher incidence of spontaneous miscarriage preliminary treatment with long acting GnRH agonist before exogenous gonadotropin stimulation : prevent premature luteinization risk poor luteal function residual GnRH agonist induced LH suppression

5.Novel gonadotropin treatment regimens

normal ovulatory cycle : preovulatory follicular development are completed while FSH levels continue a steady decline dominant follicle highly sensitive FSH development smaller less FSH sensitivity follicle in cohort atresia preovulatory phase : estrogen and FSH LH receptor granulosa cell dominant follicle

5.Novel gonadotropin treatment regimens cont.

low doses of hCG or recombinant LH can selectively promote larger follicle growth remains quite limited hypogonadotropic hypogonadism or PCOS : recombinant LH treatment (225-450 IU daily) during latter stages of follicular development can decrease the number of developing follicles little effect on circulating progesterone and testosterone concentration and risk of causing premature luteinization or other adverse effect is low

Monitoring gonadotopin therapy

To achieve ovulation but also avoid ovarian hyperstimulation and minimize the risk for multiple pregnancy serial serum estradiol measurements and ovarian ultrasonography

Serum estradiol level

follicles 10 mm estrogen estradiol exponential 2 2-3 follicle mature natural ovulatory cycle, estradiol peak 200-400 pg/ml just before LH surge existing gonadotropin stimulation regimen, best results when estradiol concentration peak 500-1,500 pg/ml, pregnancy are rare at level below 200 pg/ml

ovarian ultrasonography

antral follicles can be identified by cycle day 5-7 dominant follicle emerges by day 8-12 grows approximately 1-3 mm per day thereafter most rapidly over 1-2 days immediately preceding ovulation follicle 20-24 mm LH surge

 exogenous gonadotropin stimulating cycles : reach maturity at a smaller mean diameter Follicle <14 mm rarely ovulate 15-16 mm ovulate 40% 17-18 mm ovulate 70% 19-20 mm ovulate 80% all larger follicle will ovulate

Larger number of intermediate and small follicles also increase risk for ovarian hyperstimulation syndrome hCG risk high multiple ovulation goal of treatment is unifollicular ovulation

Result of exogenous gonadotropin treatment

successfully induce ovulation in >90% either hypogonadotropic hypogonadism or clomiphene resistant anovulation Hypogonadotropic hypogonadism Cycle fecundity rate 25%, equal or greater than normal fertile women Cumulative pregnancy rate after 6 mo. 90%
Clomiphene resistant anovulation Cycle fecundity rate 5-15% Cumulative pregnancy rate 30-60% hyperandrogenic chronic anovulation have poorest prognosis

Result of exogenous gonadotropin treatment cont.

Multiple pregnancy spontaneous 1.25% clomiphene induce 5-8% gonadotropin 15-30% Normal frequency of monozygotic twin 0.3-0.4%, increase 3 fold with exogenous gonadotropin Incidence of spontaneous miscarriage in gonadotropin induced conception cycle is 20-25%, moderately higher than general 15% clomiphene and gonadotropin congenital anomalies

Risks of exogenous gonadotropin treatment

Multiple pregnancy Ovarian hyperstimulation syndrome

Multiple pregnancy

risk twin 1.older aged 2.use of exogenous gonadotropin for ovulation induction 3.superovulation 4.ARTs 1.preterm delivery 2.low birth weight 3.gestational diabetes 4.preeclampsia 5.associated with high infant morbidity and mortality ovarian stimulation 1.cycle cancellation 2.conversion to IVF and transvaginal aspiration of excess follicles

cycle cancellation

withholding hCG 1.serum estradiol level rise above 900-1,400 pg/ml 2.ultrasonography reveals more than 4-6 follicles larger than 10-14 mm

 high order multiple pregnancy 3 1.termination of entire pregnancy 2.continuing pregnancy risk preterm birth, increase neonatal morbidity and mortality and long term disability 3.multifetal pregnancy reduction

Ovarian hyperstimulation syndrome

1.ovulation induction with exogenous

gonadotropin
2.clomiphene induced cycle 3.spontaneous pregnancy associated with condition characterized by supraphysiologic concentration of hCG (multiple gestation or molar pregnancy)

Pathophysiology of Ovarian hyperstimulation syndrome

ovary vasoactive substance vascular endothelial growth factor, element of renin-angiotensin system and other cytokine capillary permeability fluid shift from intravascular fluid to extravascular space

Risk factor of Ovarian hyperstimulation syndrome

young age low body weight PCOS higher dose of gonadotropin previous episodes of hyperstimulation increase with serum estradiol level and number of developing ovarian follicles supplemental doses of hCG are administered after ovulation for luteal phase support

symptom

Mild symptom Moderate symptom Severe symptom

Mild symptom

characterized by ovarian enlargement, lower abdominal discomfort, mild nausea and vomiting, diarrhea, and abdominal distention oral analgesic and counselling to alert affected women to sign and symptoms of progressive illness

Modarate symptom

persistent and worsening symptom or ascites progression of illness antiemetics and potent oral analgesics OPD careful monitoring of daily weights and urinary frequency, serial examination to detect increase ascites, and laboratory evaluation of Hct., serum Cr.

Severe symptom
uncommom 1% severe pain, rapid weight gain, tense ascites, hemodynamic instability, respiratory difficulty, progressive oliguria and laboratory abnormality Renal failure, ARDS, hemorrhage from ovarian rupture, and thromboembolic phenomenon are potential life threatening complication hospitalization : frequent evaluate of vital signs, daily weight, abdominal circ.,fluid intake and output and serial Hct., electrolytes, renal and liver function supportive treatment

Risk factor of ovarian hyperstimulation syndrome

1.rapid rising of serum estradiol >2,500 pg/ml 2. large number of small and intermediate sized ovarian follicles fertility drugs use among nulliparous subfertility was associated with increase incidence of borderline serous ovarian tumor but not with any invasive cancer no evidence that fertility drug use increases overall breast cancer risk

Induction of ovulation with exogenous GnRH

GnRH therapy intravenous catheter for interval of 2-3 wk. or longer pulsatile fashion low risk multiple pregnancy and ovarian hyperstimulation syndrome

Pharmacology and physiology of exogenous GnRH treatment

GnRH is administer in continuous pulsatile fashion using portable, programmable minipump IV or subcutaneous IV form dose , less cost, more physiologic and more effective rapid metabolized terminal half-life 10-40 minutes after IV administration IV form mimic pulsatile hypothalamic GnRH secretion

Indication for exogenous GnRH treatment

anovulatory infertile women with hypogonadotropic hypogonadism other ovulatory disorder PCOS hyperprolactinemia dopamine fail or can not tolerate

Exogenous GnRH treatment regimens

most effective when administered intravenously in low doses (2.5-5.0 microgram/pulse) at a constant interval (every 60-90 min) response higher dose 10-20 microgram dose Primary hypogonadotropic hypogonadism : low dose 2.5 microgram/pulse induce ovulation follicular phase LH concentration may remain lower than normal and luteal phase progesterone concentration are often reduced higher dose 5.0 micrgram/pulse

Exogenous GnRH treatment regimens cont.

Secondary idiopathic hypogonadotropic hypogonadism sensitive GnRH therapy GnRH dose PCOS pretreatment with long acting GnRH agonist (daily subcutaneous administration) for 6-8 wks. Immediately before starting pulsatile GnRH treatment

 ovulation support luteal phase 1.GnRH therapy can continue at the same or slower pulse frequency every 120-240 min. 2.small dose of hCG : 2,000 IU every 3 days 3.exogenous progesterone

Monitoring exogenous GnRH treatment

monitor superovulation time of ovulation

Results of exogenous GnRH treatment

Ovulation rate 50-80% Cycle fecundability 10-30% Risk of multiple pregnancy in GnRH induced conception cycle is comparable to that associated with clomiphene treatment (5-8%) 40-75% lower than that associated with exogenous gonadotropin therapy in anovulatory women (15%) incidence of spontaneous miscarriage in exogenous GnRH induced conception cycles is 30 %, miscarriage rate are lowest in hypogonadotropic hypogonadism less than 20% and highest in PCOS >40%

Induction of ovulation with dopamine agonists

Two most common bromocriptine and cabergoline ergot alkaloid action mimic dopamine Serum concentraton of bromocriptine peak 1-3 hr. after an oral dose of bromocriptine and very little remain in the circulation 14 hr. after administration Cabergoline is a longer acting dopamine agonist with high affinity for dopamine receptor, A single dose of cabergoline effectively inhibit prolactin secretion 7 days or longer

Mechanism of action of dopamine agonists

hyperprolactinemia hypothalamic-pituitary-ovarian axis Dopamine agonist inhibit lactotrope prolactine secretion

Indications for dopamine agonist treatment

drug of choice for hyperprolactinemic infertile women with ovulation dysfunction who wish to conceive galactorrhea normal serum prolactin level >30% of PCOS can exhibit hyperprolactinemia dopamine agonist adjavant treatment exogenous gonadotropin treatment pre-treatment dopamine agonist ovarian response exogenous gonadotropin

Dopamine agonist treatment regimen

dose euprolactinemia begins with dose of 1.25-2.5 mg, administered at bedtime to more effectively suppress normal nocturnal increase in prolactine secretion low dose GI and cardiovascular side effect Prolactin level decrease and stabilize shortly after treatment begin : prolactin level 1 wk. after treatment Cabergoline begins with dose 0.25 mg twice weekly, increase gradually thereafter about every 4 wk. until the effective dose is established

Result of dopamine agonist treatment

normalizes and maintain normal prolactin level 60-85% of hyperprolactinemic women Cyclic menses are restored 70-90%, usually within 6 wk. after treatment begin Ovulatory cycle return 50-75% of treated women with or without tumors Breast secretion typically diminish 6 wk. and complete cessation of galactorrhea generally takes about twice as long to achive

Side effects of dopamine agonist

2 Bromocriptine stimulate D1 and D2 receptor cabergoline highly affinity D2 receptor mild adrenergic side effects; dizziness, nausea, vomiting, nasal stuffiness, and orthostatic hypotension 1. low dose at start 2. taking medication with meal or snack 3. vaginal administration

Risks of dopamine agonist treatment

No evidence that dopamine agonists pose any increase risk for spontaneous miscarriage or birth defects