understanding infertility, evaluations, and treatment options
DESCRIPTION
Presentation covers 3 topics: 1) Definition of infertility with brief review of female reproduction. 2) Discussion of how fertility status is evaluated with a description of some of the tests that are performed. 3) Review of several treatment options. By Dr. Arlene Morales of Fertility Specialists Medical Center (FSMG) http://ivfspecialists.com/TRANSCRIPT
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Understanding Infertility, Evaluations,and Treatment Options
Arlene J. Morales, M.D., F.A.C.O.G.
Fertility Specialists Medical Group, Inc.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
What We Will Cover
• Introduction – What is infertility?– Briefly review female reproduction
• Evaluating fertility• Fertility testing• Treatment options
– Common procedures
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Introduction
• Definition: The inability of couples of reproductive age to establish a pregnancy within 1 year through unprotected sexual intercourse1
• In the United States, 7.3 million women (12% of women of reproductive age) had difficulty or were unable to get pregnant or carry a baby to term2
• Only 50% receive treatment
• With treatment, 2 of 3 couples will succeed
1. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2008;90(5 suppl):S60. 2. Chandra et al. Vital Health Stat 23. 2005;(25):1.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
There Are Multiple Causes of Infertility
14%
6%
6%
7%
1%
6%
11%
13%
18%
19%
Causes of Infertility
Centers for Disease Control and Prevention. 2006 Assisted Reproductive Technology Success Rates: National Summary and Fertility Clinic Reports. 2008. http://www.cdc.gov/ART/ART2006/508PDF/2006ART.pdf. Accessed April 20, 2009.
Tubal factor
Ovaluatory dysfunction
Diminished ovarian reserve
Endometriosis
Uterine factor
Male factorOther causes
Unexplained
Multiple factors(female only)
Multiple factors(male + female)
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Decline in Fertility With Age:The Fixed Ovarian Pool BecomesDepleted as Time Passes
Broekmans et al. Trends Endocrinol Metab. 2007;18:58.
0
0.2
0.4
0.6
0.8
1.0
1.2
20 25 30 35 40 45 50
Monthly Fertility Rate
Female age (y)
Rel
ativ
e ra
te
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
ART: Pregnancy and Birth Rates Still
Decrease With Women’s Age
*For consistency, all percentages are based on cycles started.Centers for Disease Control and Prevention. 2006 Assisted Reproductive Technology Success Rates: National Summary and Fertility Clinic Reports. 2008. http://www.cdc.gov/ART/ART2006/508PDF/2006ART.pdf. Accessed April 20, 2009.
Age (years)
Per
cen
t
60
50
40
30
20
10
0<21 22 24 26 28 30 32 34 36 38 40 42 44 46 48 >48
Pregnancy Live birth Singleton live birth
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Determinants of Declining FertilityWith Advancing Age in Women
• Declining oocyte number and ovulatory disturbances
• Declining oocyte quality and increasing chromosomal and genetic mutations
• Luteal phase dysfunction
• Impaired fertilization rates
• Implantation failures
• Poor-quality embryos and genetic abnormalities
• Impaired endometrial receptivity
• Higher incidence of age-related gynecologic problems, including uterine fibroids and polyps
• Declining sexuality
• Increased pregnancy wastage
• Early implantation failures and preclinical losses
• Clinical losses
• Increased incidence of general medical problems accompanying aging (eg, type 2 diabetes mellitus, hypertension)
• High incidence of obstetric complications and poor pregnancy outcomes
Pal and Santoro. Endocrinol Metab Clin North Am. 2003;32:669.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
The Female Reproductive Tract
Image on file with Organon, a part of Schering-Plough.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
The Ovary
Netter illustrations used with permission of Elsevier Inc. All rights reserved.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
The Brain Controls Reproduction
Pituitary
Hypothalamus
Image on file with Organon, a part of Schering-Plough. Netter illustration used with permission of Elsevier Inc. All rights reserved.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Menstrual Cycle
Luteal PhaseFollicular Phase
Day 1 Day 14 Days 21-22or
Days 20-24
LH Surge Implantation
Day 7
Selection ofDominant
Follicle
“Window of Receptivity”
Recruitment of Follicles
Day 28
American Society for Reproductive Medicine. Age and fertility: a guide for patients. 2003. http://www.asrm.org/Patients/patientbooklets/agefertility.pdf. Accessed April 20, 2009.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
The Hormones
• Gonadotropin-Releasing Hormone (GnRH)– Released by the hypothalamus, acts on pituitary
– Coordinated pulse frequency
• Follicle-Stimulating Hormone (FSH)– Released by the anterior pituitary, acts on ovary
• Luteinizing Hormone (LH) – Released by the anterior pituitary, acts on ovary
• Estrogen (E2)– Produced by the growing follicle, acts on endometrium
• Progesterone (P4)– Produced by the corpus luteum (CL) and placenta, acts on
endometrium
American Society for Reproductive Medicine. Age and fertility: a guide for patients. 2003. http://www.asrm.org/Patients/patientbooklets/agefertility.pdf. Accessed April 20, 2009.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
How Hormones Interact
HypothalamusHypothalamus
PituitaryPituitary
OvaryOvary
FSH & LH
Coordinated GnRH Pulses
Image on file with Organon, a part of Schering-Plough.
Estrogen
Netter illustration used with permission of Elsevier Inc. All rights reserved.
The Cycle:
...Oocyte,
...Uterus, ...Hormones
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Normal Fertilization and Implantation
Image on file with Organon, a part of Schering-Plough.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
When to Suspect a Problem
• If the woman is under 35 and has tried unsuccessfully to conceive for more than 12 months
• Or if the women is over 35 and has tried for more than6 months
• If the couple meets either of these criteria, then the couple may need to be evaluated
• Although couples frequently turn to their Ob/Gyn for initial fertility guidance, referral to an infertility specialist, a reproductive endocrinologist (RE), may be necessary
Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86(5 suppl):S264.Taylor. BMJ. 2003;327:494.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Evaluating Female FertilityClinical Need Routine Tests
First Exam • Patient history and physical exam
Ovulatory status • Midluteal serum progesterone• Ultrasound scanning• Endometrial biopsy• Basal body temperature
Ovarian reserve • Basal LH, FSH, E2, inhibin B, anti-Müllerian hormone, FSH:LH ratio• Clomiphene citrate, exogenous FSH, or GnRH antagonist testing
Uterine factors • Ultrasound scanning• Hysteroscopy• Hysterosalpingography (HSG)
Tubal factors • HSG• Fluoroscopic tubal cannulation• Chromotubation
Bowen et al. Fertil Steril. 2007;88:390. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86(5 suppl):S264. Taylor. BMJ. 2003;327:494.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Endometrial Biopsy
• Delayed endometrial maturation from inadequate P4 production by the CL could cause infertility and early pregnancy loss
• Histologic dating of the endometrium via biopsy has been used for the evaluation of CL function and diagnosis of luteal phase deficiency (LPD)
• However, a single biopsy is not sufficient to make the diagnosis
• Therefore, most REs do not believe that “histologic dating” isa good diagnostic tool
Murray et al. Fertil Steril. 2004;81:1333.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Transvaginal Ultrasound
Image on file with Organon, a part of Schering-Plough.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Hysteroscopy
Polyp
Septum
©Tim Peters and Company, Inc. Peapack, NJ 07977, USA.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Hysterosalpingography (HSG)
©Tim Peters and Company, Inc. Peapack, NJ 07977, USA.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Evaluating Male FertilityClinical Need Routine Tests
First exam • Reproductive/medical history
• Physical examination
Semen analysis • Ejaculate volume
• pH
• Sperm concentration
• Total sperm number
• Percent motility
• Forward progression
• Normal morphology
• Sperm agglutination
• Viscosity
Additional analyses • Basal hormone analysis: FSH, LH, testosterone, prolactin
• Postejaculatory urinalysis
• Ultrasonography
• Testicular biopsy/exploration
• Genetic screening
• Specialized semen and sperm analyses
Male Infertility Best Practice Policy Committee of the American Urological Association; Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86(5 suppl):S202. Taylor. BMJ. 2003;327:494.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Male Infertility
Normal sperm quality:Count: >20 × 106/mL
Morphology: >30% Motility: >50%
Image on file with Organon, a part of Schering-Plough
Male Infertility Best Practice Policy Committee of the American Urological Association; Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86(5 suppl):S202. Taylor. BMJ. 2003;327:494.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Treatment Options for Infertile CouplesCondition Treatment OptionsFemale infertility
Ovulatory failure or dysfunction OI
Tubal factor COS with IVF
Endometriosis IUI (patent tubes), or COS with IVF
Male infertility
Male subfertility IUI with or without OI
Male factor COS with ICSI
Female and/or male infertility
Unexplained IUI, COS with IVF, or ICSI
National Institute for Clinical Excellence. Fertility assessment and treatment for people with fertility problems. 2004. http://www.nice.org.uk/nicemedia/pdf/CG011fullguideline.pdf. Accessed April 20, 2009.
OI = ovulation induction; COS = controlled ovarian stimulation; IVF = in vitro fertilization;IUI = intrauterine insemination; ICSI = intracytoplasmic sperm injection.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Ovulation Induction
• OI is useful in patients with anovulatory infertility– WHO class I: hypogonadotropic hypogonadism
– WHO class II: polycystic ovary syndrome (PCOS)
• Goal– Stimulate development of a single follicle that will be able to
reach preovulatory size and rupture
• Options– Clomiphene citrate (CC)
– Gonadotropins (hMG/FSH followed hCG)
– GnRH analogue
Messinis. Hum Reprod. 2005;20:2688. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2008;90(5 suppl):S7. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86(5 suppl):S187.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Ovulation Induction: Clomiphene Citrate • CC is an antiestrogen that binds to estrogen receptors and interferes
with estrogen-negative feedback – Results in an alteration in pulsatile GnRH secretion – Leads to increases in gonadotropin secretion and follicular development
• CC is widely used for ovulation induction in women with PCOS and in couples with unexplained infertility
• CC treatment successfully induces ovulation in about 80% of properly selected candidates – Pregnancy rates are much lower (30%-40% per cycle)– 40%-45% of couples can become pregnant within 6 cycles– Failure to conceive after successfully induced ovulation is indication for
further evaluation
• Patient characteristics predictive of poor response to CC:– Hypothalamic disorder– Low estrogen levels– Obesity
American Society for Reproductive Medicine. Medications for inducing ovulation: a guide for patients. 2006. http://www.asrm.org/Patients/patientbooklets/ovulation_drugs.pdf. Accessed April 20, 2009. Case. Can Fam Physician. 2003;49:1465. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86:S187.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Limitations and Risks With CC for OI • CC is generally well tolerated, although some side effects may limit its
efficacy and safety– Short-term, reversible side effects include: hot flashes, mood swings,
visual disturbances, breast tenderness, pelvic discomfort, and nausea– The antiestrogenic effects may negatively impact the uterine lining, leading
to lower pregnancy rates– Risk of multiple pregnancy is increased– Risk of cancer is increased among women who were treated with CC
• Uterine fibroid risk increases with CC treatment• Risk of ovarian cancer increases among women treated with prolonged
CC
• Treatment should be limited to no more than 6 cycles or fewer in consideration of woman’s individual situation– Age, baseline characteristics, etc
Althuis et al. Am J Epidemiol. 2005;161:607.Case. Can Fam Physician. 2003;49:1465.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Ovulation Induction: Gonadotropin Treatment• Optimal for women who have failed CC or who cannot risk waiting • Used in women with inadequate pituitary secretion of LH and FSH
(hypogonadotropic amenorrhea) or PCOS• Agents: FSH, hCG, human menopausal gonadotropin (hMG)• Success rates
– WHO class I: 30% per cycle– WHO class II: 17% per cycle
• May include IUI or natural intercourseOI
American Society for Reproductive Medicine. Medications for inducing ovulation: a guide for patients. 2006. http://www.asrm.org/Patients/patientbooklets/ovulation_drugs.pdf. Accessed April 20, 2009. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2008;90(5 suppl):S7.
hCG
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Use of IUI in OI Protocol• Indications
– Unexplained infertility – Male subfertility—mild
oligozoospermia, asthenozoospermia, or teratozoospermia
– Failure to conceive after ovulation induction treatment
– Ejaculatory failure– Retrograde ejaculation
• Procedure– Washed prepared sperm are
deposited in the uterus just before the release of an egg or eggs in a natural or stimulated cycle
• Success rate: up to 15% per cycle
• Significant risk for multiple pregnancy
Rowell and Braude. BMJ. 2003;327:799.
Image on file with Schering-Plough/Organon.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
In Vitro Fertilization
Procedure
• Initially used in women with fallopian tube blockage or damage
• Now employed for many causes of infertility (eg, endometriosis, male factor)
• Involves– COS– Egg retrieval– Insemination, fertilization,
embryo culture– Embryo transfer– Cryopreservation of extra
embryos
Risks
• Ovarian hyperstimulation syndrome (OHSS)– Usually not serious and
resolves with outpatient management
– 1%-2% severe requiring hospitalization
– Dose-dependent, avoided by careful titration
• Anesthesia• Multiple births• Ectopic pregnancy• Cost• Psychologic distress
American Society for Reproductive Medicine. Assisted reproduction technologies: a guide for patients. 2008. http://www.asrm.org/Patients/patientbooklets/ART.pdf. Accessed April 20, 2009.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Intracytoplasmic Sperm InjectionIndications
• Very low numbers of motile sperm
• Severe teratospermia• Problems with sperm binding to
and penetrating the egg• Antisperm antibodies• Prior or repeated fertilization
failure with standard IVF methods
• Frozen sperm limited in number and quality
• Obstruction of the male reproductive tract not amenable to repair
Success Rate and Complications
• Fertilization rate: 50%-80%• Live offspring: 20%-40%
(40% in younger women; success declines with maternal age)
American Society for Reproductive Medicine. Intracytoplasmic sperm injection (ICSI). 2008. http://www.asrm.org/Patients/FactSheets/ICSI-Fact.pdf. Accessed April 20, 2009. Campbell and Irvine. Br Med Bull. 2000;56(3):616. Palermo et al. Sem Reprod Med. 2000;18(2):161.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Controlled Ovarian Stimulation: Gonadotropin Treatment • Starts with higher dose of gonadotropins than for OI (COS: 150-225 IU
of FSH; OI: 50-75 IU of FSH)• Needs GnRH analog treatment to prevent interference by endogenous
hormones• COS is followed by oocyte retrieval, IVF, and transfer of embryos
hCG
COS
Arslan et al. Fertil Steril. 2005;84(3):555.Borini and Dal Prato. Reprod Biomed Online. 2005;11:283.
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Common Procedures: COS
IVF
or
ICSI
rFSH/hMG
Day 2 or 3of menses
GnRH agonist
Cycle day21-24
Down regulation
Luteal phasesupport
Embryo TransferEmbryo Transfer
GnRH antagonist
Day 6 of FSH
rFSH/hMG
hCGhCG
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
How can the Ob/Gyn and fertilityspecialist work together to ensure that patients get the most appropriatetreatment as soon as possible?
FertilitySpecialist
Ob-Gyn Patient
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Management Algorithm for Ob/Gyn
Hanson and Dumesic. Mayo Clin Proc.1998;73:681.
Refer to fertility specialist
Female <35 years of age1 year of infertility
Female >35 years of age6 months of infertility
Abnormal
SuccessfulUnsuccessful
Initiate prenatal care
Couple attempting conception
Abnormal
Abnormal
Normal
Determine progesterone level 7 days after presumed ovulation
Anovulation or oligo-ovulation without hirsutism
Female physiology: serum-sensitive TSH, FSH, and prolactin levels
Male evaluation: semen analysis
Female anatomy: hysterosalpingography
Ovulation
Consider referral forCOS
Treatment: clomiphene citrate 50-100 mg/d orally for 5 days during menses, for 3 cycles
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Summary
• Infertility treatment protocol and success rates are highly dependent on ovarian age – Associated risk factors increase with age (eg, endometriosis) as well
as other risks (chromosomal abnormalities)
• Conduct diagnostic tests after– 1 year of infertility for woman aged <35 years
– 6 months of infertility for woman aged >35 years
• Multiple techniques exist to assess ovulatory function, and several different types of protocols treat female infertility– Most treatments have higher rates of success in younger women
• The Ob/Gyn, fertility specialist, and patient need to work together to determine reasonable expectations and optimal treatment course
Arlene J. Morales, M.D., FACOG
FER 03520 Infertility DT6 04/11/23 21:45
Thank You
Arlene J. Morales, M.D., F.A.C.O.G.Fertility Specialists Medical Group, Inc.