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Understanding Infertility, Evaluations, and Treatment Options

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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 …

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/

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  • We will start today by explaining the definition of infertility and going through a brief review of female reproduction. Then we will discuss how fertility status is evaluated and some of the tests that are performed. Finally we will talk about some of the available treatment options.
  • The definition of infertility is the inability of couples of reproductive age to establish a pregnancy within 1 year through unprotected sexual intercourse. 1 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 term. 2 (Based on data from 2002) Only half of those couples will actually seek and receive treatment, but with treatment, 2 of 3 couples will succeed in having a child. 1. Practice Committee of the American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss. Fertil Steril . 2008;90(5 suppl):S60. 2. Chandra A, Martinez GM, Mosher WD, Abma JC, Jones J. Fertility, family planning, and reproductive health of U.S. women: data from the 2002 National Survey of Family Growth. Vital Health Stat 23 . 2005;(25):1-160.
  • Information compiled by the Centers for Disease Control indicates that a large number of factors contribute to infertility among couples who ultimately use assisted reproductive technology (ART). 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.
  • Over the past few decades, postponement of childbearing has led to a decrease in family size and increased rates of age-related female subfertility. Age-related decreases in ovarian follicle numbers and a decay in oocyte quality dictate the occurrence of natural loss of fertility and, ultimately, menopause. While ART may help, it does not modify physiology. Fixed early in life: primordial germ cells arrive in the gonadal ridge by the seventh week of gestation. Total germ cell number peaks at 20 weeks of gestation! From a peak of 6-7 million, oocyte number declines to  350,000 by birth. By puberty, there are  200,000 follicles remaining in the ovary. Menopause sets in at an average age of 51 years, although the rate of the ovarian aging process is highly variable. Broekmans FJ, Knauff EA, te Velde ER, Macklon NS, Fauser BC. Female reproductive ageing: current knowledge and future trends. Trends Endocrinol Metab . 2007;18(2):58-65. McGee EA, Hsueh AJ. Initial and cyclic recruitment of ovarian follicles. Endocr Rev . 2000;21(2):200-214.
  • This graph presents the pregnancy rates, live birth rates, and singleton live birth rates for ART cycles using fresh nondonor eggs or embryos, by the age of the woman in 2006 (for consistency, all percentages are based on the number of cycles started). As you see, a woman’s ability to become pregnant and carry to term decreases dramatically after age 35. 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.
  • There are many different determinants that negatively affect fertility. The determinant with highest impact is declining oocyte number and quality, which is directly related to a woman’s age. You will notice that we mainly concentrate on the female when we discuss infertility, especially when it comes to age, because the male can produce sperm from puberty throughout his lifetime. Pal L, Santoro N. Age-related decline in fertility. Endocrinol Metab Clin North Am . 2003;32(3):669-688.
  • The female reproductive organs include the ovaries, fallopian tubes, uterus, cervix, and vagina. Each of these structures undergoes a number of physiologic changes during the menstrual cycle in response to the patterns and concentrations of the reproductive hormones to prepare for ovulation and, if the oocyte is fertilized, pregnancy.
  • This diagram shows the ovary and depicts several stages of follicular development that occur during the menstrual cycle. During the follicular phase, several follicles are recruited and undergo growth and development before one dominant follicle is selected for final maturation. These follicles secrete several hormones, but the most important is estrogen, which acts both on the brain and the endometrium. This dominant follicle will release the oocyte at ovulation and undergo further changes to become the residual structure, the corpus luteum (CL). The CL secretes the steroid progesterone, which also acts on the endometrium to prepare for implantation of a fertilized oocyte.
  • The brain is included in the reproductive system because the production and secretion of gonadotropin-releasing hormone (GnRH) and the gonadotropins are regulated by 2 key areas: the hypothalamus and a pea-sized gland under the hypothalamus, the pituitary (also known as “the master gland”). The menstrual cycle involves a complex cascade of hormonal and physiologic changes that involve the brain and the reproductive organs.
  • The average menstrual cycle lasts about 28 days and begins on the first day of a woman’s period. 1 The menstrual cycle can be broken down into 2 phases, each lasting approximately 14 days 1 : The follicular phase (first 14 days of the cycle) At the same time as the endometrial lining from the previous cycle is shed, the next wave of follicles begins to undergo maturation, and a dominant follicle is selected. Ovulation of the egg contained within this dominant follicle will occur on approximately day 14. The luteal phase (last 14 days of the cycle) The follicle that has just released the oocyte will be converted into a CL, which will begin to produce progesterone. Progesterone helps to prepare the uterus for pregnancy. The endometrium is ready to receive a fertilized oocyte only during a short window of receptivity lasting approximately 4 days (from about cycle day 20 to cycle day 24). 2 1. 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. 2. Diedrich K, Fauser BC, Devroey P, Griesinger G; Evian Annual Reproduction (EVAR) Workshop Group. The role of the endometrium and embryo in human implantation. Hum Reprod Update . 2007;13(4):365-377.
  • The entire menstrual cycle is controlled by 5 major hormones: GnRH is released from a portion of the brain, the hypothalamus, travels through a very small network of blood vessels, and acts on another portion of the brain, the anterior pituitary. GnRH is released in coordinated pulses. The amplitude and frequency of GnRH pulses are very important because they dictate the amount and ratio of other hormones, the gonadotropins, which are released from the anterior pituitary. If these pulses are too fast or too slow, the system will not function correctly. The 2 gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), are secreted by the anterior pituitary in response to the pulsatile release of GnRH. FSH acts on the ovaries to stimulate the growth of the follicles in the ovaries. LH helps to mature the oocyte, stimulates ovulation, and causes the luteinization (or conversion) of the cells in the newly ovulated follicle into a CL. Estrogen (E 2 ) is produced by the growing follicles and acts on the lining of the uterus, the endometrium, to thicken it in preparation for the potential implantation of an embryo. E 2 also feeds back to the hypothalamus and pituitary to regulate the secretion of GnRH, FSH, and LH. Progesterone (P 4 ) is produced by the CL (and placenta if a pregnancy occurs) and acts on the endometrium, causing it to become more vascular and help maintain a pregnancy. 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.
  • This is a very basic description of how the reproductive hormones interact, and represents a simplified picture of reproductive endocrinology. This graphic shows the basics of how the hormones interact and the positive and negative feedback mechanisms of the hypothalamic-pituitary-ovarian axis: Early in the menstrual cycle, GnRH is released in coordinated pulses to stimulate the production and release of FSH from the anterior pituitary. FSH travels through the bloodstream and stimulates the growth of follicles in the ovaries. As follicles grow, they produce estrogen. While the developing follicles are small, they produce low levels of estrogen, which feeds back to the hypothalamus and anterior pituitary to stimulate additional GnRH and FSH release. As the developing follicles grow, they secrete increasing amounts of estrogen until a dominant follicle is selected. This dominant follicle secretes very high levels of estrogen. The high concentrations of estrogen secreted by the dominant follicle cause a change in the pulse frequency of GnRH. The change in GnRH pulse frequency causes a shift in gonadotropin secretion from FSH to LH, which leads to the final oocyte maturation and ovulation of the dominant follicle.
  • As mentioned, the reproductive hormones act on the ovary to support oocyte growth and maturation, but these hormones also act on the endometrial lining of the uterus to prepare for the implantation of a fertilized oocyte. During the first 4 days of the menstrual cycle, the endometrial lining is sloughed away and can be seen as the menstrual flow of a period. During the next 10 days, the endometrial lining is rebuilding and thickening. Following ovulation, the uterus is preparing for the impending implantation of an embryo. If an embryo does not implant, the uterine lining will prepare to slough again and the cycle starts over.
  • In a normal cycle, a mature oocyte will be released from the ovary, and if sperm are in place in the female reproductive tract, fertilization will occur. Following fertilization, subsequent embryo development will take place, the embryo will implant in the uterus, and a pregnancy will occur. But what happens if there is 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 than 6 months, then the couple may need to be evaluated. Often the Ob/Gyn will do initial evaluations and perform first-line treatments. Depending on the findings, patients may need to be referred to an infertility specialist known as a reproductive endocrinologist. Practice Committee of the American Society for Reproductive Medicine. Optimal evaluation of the infertile female. Fertil Steril . 2006;86(5 suppl):S264-S267. Taylor A. ABC of subfertility. Making a diagnosis. BMJ . 2003;327(7413):494-497.
  • There are a number of tests that can be performed to help diagnose the cause of a patient’s infertility and help determine the course of treatment. During the first exam, the patient’s medical history will be taken, a full physical will be performed, and hormone levels will be measured. Biochemical markers such as basal LH, FSH, E 2 , inhibin B, anti-M üllerian hormone (AMH), FSH:LH ratio, and midluteal progesterone concentrations can be used to determine the patient’s ovulatory status and ovarian reserves. Other tests are also used to verify ovulatory status, ovarian reserves, and other factors that may impact the patient’s ability to conceive and carry a pregnancy to full term. The next few slides will show some examples of other tests that may be performed. Bowen S, Norian J, Santoro N, Pal L. Simple tools for assessment of ovarian reserve (OR): individual ovarian dimensions are reliable predictors of OR. Fertil Steril . 2007;88(2):390-395. Practice Committee of the American Society for Reproductive Medicine. Optimal evaluation of the infertile female. Fertil Steril . 2006;86(5 suppl):S264-S267. Taylor A. ABC of subfertility. Making a diagnosis. BMJ . 2003;327(7413):494-497.
  • Delayed endometrial maturation due to inadequate P 4 production by the CL could be a cause of infertility and early pregnancy loss. Histologic dating of the endometrium via biopsy has been used for the evaluation of CL function and the diagnosis of luteal-phase deficiency (LPD). During an endometrial biopsy, several scrapings of the uterine lining (similar to a pap smear) are taken 2 to 3 days before the patient’s period, and the samples are sent to a pathologist who evaluates them in an attempt to date the endometrium. A single biopsy is not sufficient to make the diagnosis of LPD or to guide the clinical management of women with reproductive failure because histologic endometrial dating does not have the necessary accuracy or precision. As a result, most REs do not think that “histologic dating” is a helpful diagnostic tool. Murray MJ, Meyer WR, Zaino RJ, et al. A critical analysis of the accuracy, reproducibility, and clinical utility of histologic endometrial dating in fertile women. Fertil Steril . 2004;81(5):1333-1343.
  • Here we see a diagram of a transvaginal ultrasound. This procedure is used to evaluate the ovaries and uterus for the presence of polycystic ovaries or fibroids. (Transvaginal ultrasound is also used to help guide the needle during egg retrieval and during embryo transfer.)
  • Here we see how a small camera called a hysteroscope is used to look inside the uterus. We see some examples of abnormalities that may be found: In the picture on the upper right, we can see fibroids inside the uterus. On the lower left, the image shows a septum inside the uterine cavity. The image on the lower right displays the presence of an intrauterine polyp.
  • Tests to assess the patient’s tubal status and uterine cavity can be performed by hysterosalpingography (HSG), hysterosalpingo-contrast sonography (HyCoSy), or laparoscopy and dye test with hysteroscopy. This slide shows 2 examples of HSG. HSG and HyCoSy are “dynamic” outpatient investigations conducted via injection of contrast medium into the uterus to show the shape of the uterine cavity. HSG uses real-time x-ray imaging to follow the flow of contrast into the tubes and peritoneal cavity. HyCoSy uses ultrasonography and can provide additional information because an ultrasound scan of the pelvis performed at the same time allows the detection of fibroids or polycystic ovaries. The first picture shows an apparently normal uterus with open fallopian tubes. The second picture is an abnormal finding showing hydrosalpinges (water-filled tubes) that are extremely dilated. Taylor A. ABC of subfertility. Making a diagnosis. BMJ . 2003;327(7413):494-497.
  • Ideally, evaluation of the male partner should be conducted at the same time as the female partner to determine appropriate management of the couple as well as to spare the couple the distress of attempting ineffective therapies. During the first exam, the male partner’s reproductive medical history will be taken and a full physical will be performed with a semen analysis. If possible, 2 semen analyses should be conducted, separated by a period of 1 month. Semen analysis provides information on semen volume and sperm quality and quantity. Analysis of basal hormone concentrations may provide information on abnormal spermatogenesis. Hormonal abnormalities of the hypothalamic-pituitary-testicular axis are rare, but are a possible cause of male infertility. Testicular biopsy or examination and ultrasonography may reveal pathologies or obstructions. In addition, further specialized genetic and sperm analyses may be useful in a small number of patients. Male Infertility Best Practice Policy Committee of the American Urological Association; Practice Committee of the American Society for Reproductive Medicine. Report on optimal evaluation of the infertile male. Fertil Steril . 2006;86(5 suppl):S202-S209. Taylor A. ABC of subfertility. Making a diagnosis. BMJ . 2003;327(7413):494-497.
  • Semen analysis is a noninvasive test and can yield a great deal of information. Sperm counts, motility, and morphologic analysis can give an indication of semen quality and can provide some information regarding treatment options, such as whether in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) will be required. Male Infertility Best Practice Policy Committee of the American Urological Association; Practice Committee of the American Society for Reproductive Medicine. Report on optimal evaluation of the infertile male. Fertil Steril . 2006;86(5 suppl):S202-S209. Taylor A. ABC of subfertility. Making a diagnosis. BMJ . 2003;327(7413):494-497.
  • Different treatment options are suitable for women and men with infertility due to different causes. Ovulatory failure or dysfunction can be treated with ovulation induction (OI); tubal factor infertility or endometriosis can be treated with controlled ovarian stimulation (COS) and IVF. Male subfertility can be treated with intrauterine insemination (IUI) with or without OI. Unexplained male or female infertility can be treated with IUI, COS with IVF, or ICSI. All conditions need to be considered on a case-by-case basis (eg, not all patients with endometriosis should be treated with IVF; if analysis indicates the patient has patent tubes, these patients may first try IUI). 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 is recommended for patients with anovulatory infertility. WHO class I: hypogonadotropic hypogonadal anovulation (hypothalamic amenorrhea) These women have low or low-normal serum FSH concentrations and estradiol concentrations due to decreased hypothalamic secretion of GnRH or a pituitary that is unresponsive to GnRH. WHO class II: normogonadotropic normoestrogenic anovulation This group includes women with polycystic ovary syndrome (PCOS). Some ovulate occasionally, especially those with oligomenorrhea. These women may secrete normal amounts of gonadotropins and estrogens, although FSH secretion during the follicular phase of the cycle is subnormal. The goal of treatment is selection of a single follicle that will be able to reach preovulatory size and rupture. Treatment options for ovulation induction include clomiphene citrate (CC) or gonadotropins (hMG/FSH followed by hCG). Aromatase inhibitors and insulin sensitizers are not used commonly and are not indicated for OI. Following OI, fertilization can be achieved with natural fertilization or IUI. Messinis IE. Ovulation induction: a mini review. Hum Reprod . 2005;20(10):2688-2697. Practice Committee of the American Society for Reproductive Medicine. Use of exogenous gonadotropins in anovulatory women: a technical bulletin. Fertil Steril . 2008;90(5 suppl):S7-S12. Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in women. Fertil Steril. 2006;86(5 suppl):S187-S193.
  • 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. The key is “properly selected candidates.” Successful ovulation does not necessarily translate into a pregnancy. 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 AM. Infertility evaluation and management. Strategies for family physicians. Can Fam Physician . 2003;49:1465-1472. Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in women. Fertil Steril. 2006;86(5 suppl):S187-S193.
  • CC is generally well tolerated although some side effects limit efficacy and raise safety concerns. 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. Transvaginal ultrasound assessment of endometrial thickness before ovulation can indicate thin endometrium (<6 mm). This is a repetitive effect, so patients with a diagnosis of thin endometrium during their first cycle are not candidates for further CC treatment. Risk of multiple pregnancy is increased with CC. Risk of cancer is increased among women who were treated with CC. Uterine cancer risk increases with more than 6 cycles of CC treatment. Risk of ovarian cancer increases among women treated with CC for more than 12 cycles. Treatment should be limited to no more than 6 cycles. The chance of success declines greatly after multiple cycles. Because of the potential side effects associated with CC, all patients should be monitored to assess response to treatment. Without ultrasound monitoring, the number of CC cycles should be limited to 3 (or fewer), and early referral should be considered. Althuis MD, Moghissi KS, Westhoff CL, et al. Uterine cancer after use of clomiphene citrate to induce ovulation. Am J Epidemiol . 2005;161(7):607-615. Case AM. Infertility evaluation and management. Strategies for family physicians. Can Fam Physician . 2003;49:1465-1472.
  • Gonadotropin therapy should only be administered under the direction of REs who have the requisite training and experience in its use. Exogenous gonadotropin therapy is optimal for women who have failed CC or who cannot risk waiting (due to age, known male infertility, etc). Used in women with inadequate pituitary secretion of LH and FSH (hypogonadotropic amenorrhea) or PCOS Other causes for infertility should be excluded before gonadotropins are administered. 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 intercourse This slide depicts a typical gonadotropin (low-dose FSH) ovulation induction protocol, with the aim of producing a single oocyte (multiple follicular growth for ARTs such as IVF and ICSI will be discussed later). 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. Use of exogenous gonadotropins in anovulatory women: a technical bulletin. Fertil Steril . 2008;90(5 suppl):S7-S12.
  • IUI is usually the first step in treating couples with unexplained infertility. Also useful for some types of male infertility or subfertility. It is simpler, less expensive, and less invasive than IVF or ICSI. The technique is most effective when it is combined with mild stimulation using gonadotropins. For IUI, a sample of washed, prepared, motile sperm is deposited in the uterus just before the release of an egg or eggs in a natural or a stimulated cycle. Pregnancy rates vary considerably, but are generally around 15% per cycle. Multiple pregnancy is a risk, therefore the cycle should be cancelled if there are more than 3 developing follicles if oocyte retrieval is not planned. Factors that affect the success of IUI include the cause of infertility, ages of partners, sperm quality, and duration of infertility. Rowell P, Braude P. Assisted conception. I — General principles. BMJ. 2003;327(7418):799-801.
  • Initially, IVF was used to treat women with blocked, damaged, or absent fallopian tubes. Today, IVF is used to treat many causes of infertility, such as endometriosis and male factor, or when a couple’s infertility is unexplained. The basic steps in an IVF treatment cycle are COS, egg retrieval, insemination, fertilization, embryo culture, and embryo transfer. The medical risks of ART depend upon each specific step of the procedure and include: ovarian hyperstimulation syndrome (OHSS), complications associated with egg retrieval, ectopic pregnancy, and miscarriage. OHSS is usually not serious and resolves with outpatient management, although 1%-2% of cases are severe and require hospitalization. OHSS is dose-dependent and is avoided by careful titration. Some may view the increased probability of multiple births as a risk associated with IVF. This procedure is also costly and may result in significant psychologic distress for couples. 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.
  • Indications for ICSI include very low numbers of motile sperm, severe teratospermia, problems with sperm binding to and penetrating the egg, antisperm antibodies thought to be the cause of infertility, prior or repeated fertilization failure with standard IVF methods, frozen sperm limited in number and quality, and obstruction of the male reproductive tract not amenable to repair. The fertilization rate with ICSI can be as high as 50%-80%, and live offspring are obtained in approximately 20%-40% of patients. American Society for Reproductive Medicine. Intracytoplasmic sperm injection (ICSI). 2008. http://www.asrm.org/Patients/FactSheets/ICSI-Fact.pdf. Accessed April 20, 2009. Campbell AJ, Irvine DS. Male infertility and intracytoplasmic sperm injection (ICSI). Br Med Bull . 2000;56(3):616-629. Palermo GD, Neri QV, Hariprashad JJ, Davis OK, Veeck LL, Rosenwaks Z. ICSI and its outcome. Semin Reprod Med. 2000;18(2):161-169.
  • COS is used in protocols involving IVF to create multiple oocytes for eventual insemination and implantation. In order to initiate and sustain the growth and development of multiple follicles (rather than to support a single ovulation), higher doses of gonadotropins are required. COS requires higher doses of gonadotropins than OI (150-225 IU of FSH vs 50-75 IU for OI). COS also requires cotreatment with a GnRH analog to prevent interference of COS by endogenous hormones. Arslan M, Bocca S, Mirkin S, Barroso G, Stadtmauer L, Oehninger S. Controlled ovarian hyperstimulation protocols for in vitro fertilization: two decades of experience after the birth of Elizabeth Carr. Fertil Steril . 2005;84(3):555-569. Borini A, Dal Prato L. Tailoring FSH and LH administration to individual patients. Reprod Biomed Online . 2005;11(3):283-293.
  • There are 2 types of GnRH analog: GnRH agonists bind to GnRH receptors on the anterior pituitary and elicit the release of FSH and LH, which initially cause a flare response then a downregulation of the endogenous GnRH, FSH, and LH. GnRH antagonists bind to GnRH receptors and do not elicit a release of hormones, but instead cause an almost immediate downregulation of endogenous hormones. This diagram illustrates a treatment regimen with GnRH antagonists and a “long protocol” with a GnRH agonist in patients undergoing COS with recombinant FSH. In the antagonist protocol, gonadotropins are started on day 2 or 3 of the cycle, then the antagonist is started on day 6 and continues until the day of hCG administration. In the “long agonist” protocol, the agonist is started on day 21 to 24 of the previous cycle and continues through the day of hCG administration with gonadotropins started on day 2 or 3 of the treatment cycle. After hCG, the oocytes are retrieved, and fertilized in the laboratory using either IVF or ICSI, and then the embryos are transferred back into the patient. In most cases, luteal phase progesterone support is given.
  • How can the Ob/Gyn and fertility specialist work together to ensure that patients get the most appropriate treatment as soon as possible?
  • This treatment algorithm from the Mayo Clinic identifies specific situations in which referral to a fertility specialist is indicated. TO SPEAKER: Referral from fertility specialist back to Ob/Gyn should be discussed here as well. Please indicate how you manage patients after successful IVF. Hanson MA, Dumesic DA. Initial evaluation and treatment of infertility in a primary-care setting. Mayo Clin Proc . 1998;73(7):681-685.
  • Transcript

    • 1. Understanding Infertility, Evaluations, and Treatment Options Arlene J. Morales, M.D., F.A.C.O.G . Fertility Specialists Medical Group, Inc.
    • 2. What We Will Cover
      • Introduction
        • What is infertility?
        • Briefly review female reproduction
      • Evaluating fertility
      • Fertility testing
      • Treatment options
        • Common procedures
    • 3. Introduction
      • Definition: The inability of couples of reproductive age to establish a pregnancy within 1 year through unprotected sexual intercourse 1
      • 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 term 2
      • 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.
    • 4. There Are Multiple Causes of Infertility 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 factor Other causes Unexplained Multiple factors (female only) Multiple factors (male + female)
    • 5. Decline in Fertility With Age: The Fixed Ovarian Pool Becomes Depleted as Time Passes Broekmans et al. Trends Endocrinol Metab. 2007;18:58. Monthly Fertility Rate Female age (y) Relative rate
    • 6. 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) Percent 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
    • 7. Determinants of Declining Fertility With 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.
    • 8. The Female Reproductive Tract Image on file with Organon, a part of Schering-Plough.
    • 9. The Ovary Netter illustrations used with permission of Elsevier Inc.  All rights reserved.
    • 10. 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.
    • 11. Menstrual Cycle Luteal Phase Follicular Phase Day 1 Day 14 Days 21-22 or Days 20-24 LH Surge Implantation Day 7 Selection of Dominant 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.
    • 12. 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.
    • 13. How Hormones Interact Hypothalamus Pituitary Ovary Coordinated GnRH Pulses Image on file with Organon, a part of Schering-Plough. FSH & LH Estrogen
    • 14. Netter illustration used with permission of Elsevier Inc.  All rights reserved. The Cycle: ...Oocyte, ...Uterus, ...Hormones
    • 15. Normal Fertilization and Implantation Image on file with Organon, a part of Schering-Plough.
    • 16. 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 than 6 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.
    • 17. Evaluating Female Fertility 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.
      • HSG
      • Fluoroscopic tubal cannulation
      • Chromotubation
      Tubal factors
      • Ultrasound scanning
      • Hysteroscopy
      • Hysterosalpingography (HSG)
      Uterine factors
      • Basal LH, FSH, E 2 , inhibin B, anti-M ü llerian hormone, FSH:LH ratio
      • Clomiphene citrate, exogenous FSH, or GnRH antagonist testing
      Ovarian reserve
      • Midluteal serum progesterone
      • Ultrasound scanning
      • Endometrial biopsy
      • Basal body temperature
      Ovulatory status
      • Patient history and physical exam
      First Exam Routine Tests Clinical Need
    • 18. 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” is
      • a good diagnostic tool
      Murray et al. Fertil Steril . 2004;81:1333.
    • 19. Transvaginal Ultrasound Image on file with Organon, a part of Schering-Plough.
    • 20. Hysteroscopy Polyp Septum ©Tim Peters and Company, Inc. Peapack, NJ 07977, USA.
    • 21. Hysterosalpingography (HSG) ©Tim Peters and Company, Inc. Peapack, NJ 07977, USA.
    • 22. Evaluating Male Fertility 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.
      • Basal hormone analysis: FSH, LH, testosterone, prolactin
      • Postejaculatory urinalysis
      • Ultrasonography
      • Testicular biopsy/exploration
      • Genetic screening
      • Specialized semen and sperm analyses
      Additional analyses
      • Ejaculate volume
      • pH
      • Sperm concentration
      • Total sperm number
      • Percent motility
      • Forward progression
      • Normal morphology
      • Sperm agglutination
      • Viscosity
      Semen analysis
      • Reproductive/medical history
      • Physical examination
      First exam Routine Tests Clinical Need
    • 23. Male Infertility Normal sperm quality: Count: >20 × 10 6 /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.
    • 24. Treatment Options for Infertile Couples 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. Condition Treatment Options Female 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
    • 25. 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.
    • 26. 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.
    • 27. 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.
    • 28. 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 intercourse
      OI 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
    • 29. 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.
    • 30. 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.
    • 31. Intracytoplasmic Sperm Injection
      • Indications
      • 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.
    • 32. 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.
    • 33. Common Procedures: COS IVF or ICSI rFSH/hMG Day 2 or 3 of menses GnRH agonist Cycle day 21-24 Down regulation Luteal phase support Embryo Transfer GnRH antagonist Day 6 of FSH rFSH/hMG hCG
    • 34. How can the Ob/Gyn and fertility specialist work together to ensure that patients get the most appropriate treatment as soon as possible? Fertility Specialist Ob-Gyn Patient
    • 35. Management Algorithm for Ob/Gyn Hanson and Dumesic. Mayo Clin Proc .1998;73:681. Refer to fertility specialist Female <35 years of age 1 year of infertility Female >35 years of age 6 months of infertility Abnormal Successful Unsuccessful 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 Treatment: clomiphene citrate 50-100 mg/d orally for 5 days during menses, for 3 cycles Ovulation Consider referral for COS
    • 36. 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
    • 37. Thank You Arlene J. Morales, M.D., F.A.C.O.G. Fertility Specialists Medical Group, Inc.