Infertility: The inability to conceive following 12 months of regular coitus without contraception. In couples who conceive normally, 50% do so following 3 tries whereas about 92% conceive following 12 attempts.
Fecundity: The monthly probability of pregnancy. (Normally 20-25% at best)
Primary infertility: Conception has never taken place.
Secondary infertility: At least one previous conception has been documented.
Sterility: The etiology of infertility is established and there is no possibility for conception.
Over the past two decades, the number of patient visits for infertility have soared. This does not appear to be caused by an increased proportion of infertility within age groupings. Rather, factors contributing to the demand include: a higher absolute number of couples of reproductive age ("baby boomers"), decreasing availability of babies for adoption (largely due to legalized abortion and increasing social acceptance of single parenthood), less stigma regarding infertility, increasing tubal disease due to sexually transmitted disease, and better and more plentiful medical care providers for infertility services. However, the most important contributor to the increased prevalence of infertility visits is delayed childbearing with consequent attrition of ovarian function.
Approximately 10-15% of all married couples in the United States are infertile. A systematic approach should be used to evaluate the cause(s) of infertility for a couple, while the emotional stress that accompanies infertility for both partners must be constantly addressed.
The etiology of infertility can be divided into three major categories: (1) female factor, (2) male factor, and (3) undetermined etiology. Approximately 40% of infertility cases, where the etiology has been determined, are due to female factor, 40% to male factor, and the remaining 20% are due to mixed male/female factors. In 10-20% of couples presenting for evaluation, no diagnosis can be made after standard investigation (unexplained infertility).
Investigation of infertility should be designed to be completed as efficiently as possible. All couples should have a complete history and physical. The most information can be obtained if both partners are present initially. A sexual history should be obtained, including the frequency and timing of intercourse, the use of potentially spermicidal lubricants and a complete menstrual history.
Female Infertility Etiologies
The entire reproductive axis (hypothalamus, pituitary, ovary, pelvis, fallopian tubes, uterus, and vagina) must be intact and integrated for the success of the reproductive system. Systematic consideration of major risk factors for each component should be considered during history-taking. Examples of some of the principal dysfunctions for each component of the reproductive system are given:
Sperm-childhood mumps, testicular injury/sexually transmitted diseases, varicocele, sexual dysfunction, exposure to toxins, endocrinopathies
Cervix- history of diethylstilbesterol exposure, previous cervical surgery
Vagina- embryologic malformations e.g. imperforate hymen
Systemic disease- diabetes, renal failure, thyroid dysfunction, anorexia nervosa, etc.
Review of Section I
Be aware of the most important factors in society that have contributed to infertility as major health care concern.
Realize that each anatomical component of the reproductive system must function appropriately for a successful pregnancy; and the easiest way to take a careful history is to consider each component systematically
The goals of this section are to learn to look for clues on physical examination to common infertility causes. Also, the basic tests used to evaluate each component of the reproductive system will be reviewed.
As with history taking, the physical examination is best directed toward uncovering manifestations of pathology involving each individual component of the reproductive system. In particular, attention is paid to the patient's weight, thyroid palpation, evidence of acne, hirsutism and seborrhea, as well as a search for galactorrhea. The degree of development of secondary sexual characteristics is also noted. Pelvic exam offers many clues including assessment of ovarian estrogen production (via observation of cervical mucus production and vaginal cytology), Müllerian abnormalities, leiomyomata uteri, and other pelvic masses and observation of any pelvic pain. A nonmobile retroverted uterus may signify the presence of pelvic adhesions from previous PID, surgeries, appendicitis or endometriosis that are fixing the uterus in the pelvic cul-de-sac.
Laboratory Investigation of Infertility
Rubella immunity status, chlamydia and gonorrhea cultures are generally pursued on the initial visit. Folate supplementation should be considered if an inadequate diet is ascertained (ingesting 0.4 mg of folic acid daily before conception, decreases the probability of a neural tube defect by 50%). Then, an efficient general approach is to begin with a semen analysis followed by presumptive documentation of ovulation usually by temperature charting, and an hysterosalpingogram (HSG). Attention must be paid to the time during the menstrual cycle when the tests are performed since most have an optimal window during which they should be done. Depending on the outcome of the aforementioned tests, the following additional tests may be offered: endometrial biopsies to establish the diagnosis of inadequate luteal phase and, a postcoital test to determine sperm survival and movement within cervical mucus, and lastly, diagnostic laparoscopy.
Examination of Semen
Semen analysis should be the first step in the investigation before expensive and invasive female testing is performed. Semen specimens are best collected at the andrology lab. If this is not possible, specimens can be collected at home if they can be brought to the laboratory within 3O minutes. The semen should be collected by masturbation in a clean, detergent-free container. The interval of abstinence should be 48 to 72 hours. Since most of the spermatozoa are found in the first milliliter of the ejaculate, the man should be instructed to be careful to include this fraction.
At least two specimens should be examined at least several weeks apart since there can be considerable variability in quality. Like the female, the entire male reproductive axis must be evaluated depending upon the particular sperm abnormality. Abnormal results deserve referral to a urologist skilled in the male infertility evaluation.
While the individual parameters of the semen analysis are not particularly sensitive predictors of fertility, the overall semen quality does have predictive value. Minimum normal values have been suggested: sperm concentration > 20 million per ml, total count > 60 million, ejaculate volume > 1.5 ml, total motile count > 30 million, viable sperm > 50%, normal shapes (morphology) > 60%.
A host of specialized sperm function tests are available when indicated, for example:
Antisperm antibody assays
Hamster egg penetration test (HEPT)- to predict fertilizing capability of spermatozoa
Hypoosmotic swelling test (HOS)- to assess sperm membrane function
Presumptive Documentation of Ovulation
The vast majority of women who give a history of regular menstrual cycles combined with premenstrual symptoms are probably ovulating. When in doubt, several practical tests offer presumptive evidence of ovulation: BBT, serum progesterone, and urinary LH surge testing. Endometrial biopsies and serial ultrasound examinations to ascertain the collapse of ovarian follicles are other ways to make the presumptive diagnosis of ovulation, but are less practical.
Presumptive Tests of Ovulation
Basal body temperature charting
Mid-luteal phase serum progesterone concentration
Urinary LH home test kits
Serial ovarian ultrasonography
Basal Body Temperature
Under the influence of circulating progesterone, the BBT rises in the luteal phase of the cycle. A mean increase of at least 0.4F over the proliferative-phase temperature is considered normal. The patient should be instructed to take her temperature each morning prior to getting out of bed. The BBT is free, and answers the question of whether there is ovulation or not for the majority of women. Also, the length of the luteal phase can be assessed. Drawbacks include the fact that it can not predict prospectively when ovulation will occur, and it can be bothersome to record. Digital electronic thermometers have made this early morning task more palatable.
A single serum progesterone value above 4 ng/ml obtained between days 19 and 23 of the menstrual cycle is presumptive evidence of ovulation.
Urinary LH Surge Testing
Serum estradiol is released from ovarian follicles in increasing amounts during the follicular phase. When the serum estradiol concentration exceeds a threshold level for a particular duration, positive feedback to the hypothalamic-pituitary axis initiates the release of a surge of LH. This LH surge triggers the events leading to ovulation approximately 40 hours after the start of the surge. LH is excreted into the urine where is can be measured simply by any number of commercially available ELISA home test kits. The major advantage over BBTs and serum progesterone determinations is the ability to prospectively predict the presence and timing of ovulation. LH kits (Ovuquick brand) are used in our clinic twice daily to ascertain optimal timing of artificial inseminations.
When a woman is found to be anovulatory, the underlying etiology must be sought and corrected if possible. This evaluation is detailed in the lecture on amenorrhea. In brief, some of the more common causes of anovulation include: extremes of weight, polycystic ovary syndrome (chronic hyperandrogenic anovulation), emotional stress, medications, systemic illness, and structural lesions of the hypothalamic-pituitary-ovarian axis. The initial blood evaluation includes obtaining TSH and prolactin values routinely and an FSH if ovarian failure is suspected.
Total testosterone and DHEAS are obtained if a hyperandrogenic condition is suspected clinically.
In most clinics, 30-40% of female infertility can be attributed to the pelvic abnormalities (such as tubal occlusion, adhesions, and endometriosis).
An evaluation of the patency of the fallopian tubes involves transuterine contrast instillation under fluoroscopic visualization. The study should be performed in the follicular phase of the cycle prior to ovulation. Water-soluble contrast material is generally used as it offers better detail and less risk than oil-based contrast of embolism and pelvic granulation. An HSG should be obtained relatively early in the infertility investigation following semen analysis. HSG also serves to assess the contour and adequacy of the uterine cavity. Pathology such as intrauterine leiomyomata, polyps and synechiae (Asherman's Syndrome) and well as embryologically abnormal or abnormal DES-exposed uterine cavities can be evaluated.
The couple is asked to have intercourse at least eight hours prior to but less than 24 hours prior to presenting to clinic. Postcoital testing (PCT) should be performed at midcycle when cervical mucus has a high water content secondary to the midcycle estrogen surge. At other times the mucus is thick and doesn't allow spermatozoa to penetrate. The sperm are then destroyed by the acidic vaginal environment.
Several characteristics will indicate whether the timing of the sample and the quality of the mucus is good. Copious amounts of alkaline mucus are generally observed emanating from the cervix at midcycle. A sample of cervical mucus is aspirated and placed on a glass slide. A cover slip is applied and lifted. The degree to which the mucus stretches (the spinnbarkeit) is measured. Columns of 8 or more centimeters is considered optimal. Good mucus appears acellular microscopically, and when dried the high sodium chloride content of midcycle mucus precipitates into a microscopic fernleaf-like pattern.
In a normal PCT, there should be at least several progressively motile spermatozoa per high powered field. If only a few dead sperm or no sperm are found, the most common reason is a poorly timed PCT. Other reasons include oligospermia, inadequate coital technique, hypospadias, antisperm antibodies or possibly inherent "hostile" mucus. When sperm are seen to clump together and flagellate without progressive motility, this is often associated with the presence of antisperm antibodies originating either from the mucus or the semen. This test should not be used in place of a good semen analysis. The PCT is now used sparingly due to its poor predictive value for conception, but it remains a reasonable screen for antisperm antibodies.
Approximately one week after ovulation, the now fertilized ovum (zygote), implants. The endometrium must be of sufficient quality to allow implantation. If not, it is termed luteal phase inadequacy (LPI) or luteal phase defect (LPD)-- a rare cause of infertility. Correct maturation of endometrium requires sufficient sequential hormonal stimulation, primarily with progesterone, as well as normal end organ responsiveness to these signals. Therefore, a single progesterone assay alone is insufficient to diagnose LPI. Furthermore, it is important to differentiate between inadequate luteal phase and short luteal phase. In a short luteal phase, the duration of BBT temperature rise is less than ten days. Shortened luteal phases are not associated with infertility.
Histological "dating" of the endometrium (based on the development of endometrial glands and stroma) can assess maturation. It has become the principal means of diagnosing LPI. Optimally, an
office biopsy performed with a disposable Pipelle
should sample endometrium from high in the uterus as soon before the onset of menses as possible. This allows the full effect of the hormonal stimulation during that menstrual cycle to exert its effect on the endometrium. When the histologic appearance of the endometrium shows a discrepancy of 2 or more days from the norm for the day on which the biopsy was taken, then the procedure is repeated in the subsequent cycle. Two such out-of-phase biopsies establishes the diagnosis of luteal phase inadequacy. Due to the rarity of LPI and the inherent inaccuracy and inconvenience of pursuing the diagnosis, biopsies are now done only when there are risk factors for LPI such as hyperprolactinemia, or when other infertility factors have be ruled out.
Diagnostic laparoscopy is an outpatient surgical technique in which a fiberoptic scope, is inserted through a 1 cm incision into the abdominal cavity to inspect the pelvis under general anesthesia. A number of surgical procedures can also be performed through accessory abdominal incisions using the scope for visualization. Dye can be passed through a canula via the cervix transvaginally. Patent Fallopian tubes exhibit the passage of dye through the fimbriated ends seen laparoscopically. During the procedure an hysteroscope can also be used to examine the uterine cavity. (This is an even more sensitive test than the hysterosalpingogram.)
Due to the expense and invasiveness, diagnostic laparoscopy is reserved as the last step of an infertility workup if no other salient etiologies are identified, and if conservative treatments are unsuccessful. In some circumstances, a minimally invasive laparoscopy procedure can be done under local analgesia. By this point in the evaluation, pelvic pathology (including adhesions and endometriosis) is identified in up to half of diagnostic laparoscopies.
Review of Section II
In evaluating the causes of infertility, it is helpful to consider the reproductive system segmentally such that no stone is unturned. Think of the hypothalamic, pituitary, peritoneal, ovarian, tubal, uterine, and vaginal compartments as well as systemic illnesses that can contribute to infertility. Each compartment has its typical dysfunctions and tests.
Assess rubella status, rule out STDs, folate supplementation.
Assure good general physical and emotional health.
Goals of this section are to understand the tools available to treat or circumvent the specific etiologies ascertained during the evaluation.
Therapy depends upon the etiologies identified. Anatomical defects, such as damaged tubes and Mullerian anomalies, are corrected surgically if possible. Endocrinopathies and systemic illnesses are treated specifically. For example, luteal phase insufficiency may often be corrected by supplementing progesterone during the luteal phase, and ovulation may resume spontaneously when a hyperprolactinemic woman is treated with the dopamine agonist bromocriptine.
Approximately 10-15% of infertile females are anovulatory. If potential causes of anovulation have been addressed and the woman remains anovulatory, attempts at medical induction of ovulation are reasonable. Furthermore, when the etiology of delayed fertility can not be identified after complete evaluation, and the ovaries are known not to have undergone premature failure, ovulation induction may also be attempted empirically ("superovulation"). The rationale is to drive more than one oocyte to ovulate with each cycle in order to increase the odds of a pregnancy. Likewise, intrauterine insemination of washed sperm increases the number of male gametes potentially reaching the oocyte(s).
A number of medications have been used to help initiate ovulation including clomiphene citrate, human menopausal gonadotropins (hMG), GnRH, glucocorticoids and bromocriptine mesylate.
Clomiphene Citrate- Relatively inexpensive, taken by mouth with few side effects (except a multiple gestation rate of 7% in anovulatory women and the rare possibility of inducing hyperstimulation syndrome). Requires an intact hypothalamic-pituitary-ovarian axis. Mechanism of action is primarily within the hypothalamus as an "antiestrogen". It occupies estrogen receptors and "deceives" the hypothalamus into sensing a low estrogen environment. The hypothalamus in turn signals the pituitary via pulsatile GnRH to increase gonadotropin (FSH and LH) release to produce more follicular development and subsequent estrogen release. With an intact hypothalamic-pituitary axis, clomiphene has been successful in inducing ovulation in over 90% of cases. However, pregnancy rates approach only 65%. Eighty percent of patients treated with clomiphene who get pregnant do so within three cycles of therapy. Therefore judicious, limited use under physician care is recommended Be aware that higher doses or prolonged usage can exert antiestrogen effects by thinning the endometrium and thickening cervical mucus and therefore can be counterproductive.
Human menopausal gonadotropins (hMG; Pergonal, Humegon, Metrodin, Fertinex)- Extremely expensive, given daily IM (the highly purified gonadotropin medication, Fertinex, is given SQ), and involves much more risk. The multiple gestation rate is about 15-35%, and overdosage may produce a potentially life-threatening ovarian hyperstimulation syndrome. Therefore, close monitoring with serial ovarian ultrasound and serum estradiol levels is necessary. hMG consists of LH and FSH, therefore it can bypass a non-functional hypothalamic-pituitary axis. Recombinant FSH (Gonal F) is used as above with some risks but has no contaminating protein found in the menopausal gonadotropins.
GnRH- Must be given subcutaneously or IV via a continuous pump. Therefore it is cumbersome and expensive. It requires an intact pituitary ovarian axis. It has few risks.
Glucocorticoids- Act by suppressing ACTH and therefore adrenal androgen production. This may occasionally be helpful in facilitating ovulation because circulating androgens cause ovarian follicular atresia. Used primarily in polycystic ovary syndrome with a component of elevated adrenal androgen secretion, and in women with congenital adrenal hyperplasia.
Bromocriptine mesylate (Parlodel)- Anovulatory women with hyperprolactinemia should be treated initially with bromocriptine before considering ovulation induction medications. Excess prolactin inhibits normal hypothalamic pulsatile GnRH release.
A reasonable strategy in some circumstances is to attempt to compel more than the usual one oocyte to ovulate, by using ovulation induction medications. This is termed "superovulation" and is a tactic often used for couples with unexplained infertility and other situations of low estimated fecundity prior to resorting to expensive artificial reproductive technologies.
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Endometriosis is the ectopic growth of endometrium. It is diagnosed by the histologic confirmation of both endometrial glands and stroma in an ectopic location.
Establishing the diagnosis usually requires laparoscopy. Common symptoms may include infertility, dyspareunia, dysmenorrhea and dyschezia. Common sites include ovaries, broad ligament and pelvic peritoneum, cul-de-sac and bowel. The ectopic tissue is hormonally responsive, growing in the presence of estrogen. Sloughing endometriosis may result in pelvic lesions of a variety of colors, older lesions appear as "gunpowder" lesions due to sequestered hemosiderin. Endometriosis may incite inflammation with resulting adhesion formation. Such adhesions can distort the delicate reproductive anatomical relationships resulting in infertility. Endometriosis is clinically staged into minimal, mild, moderate and severe categories (stages I-IV).
Although found in approximately 5-10% of the general population, endometriosis has been noted in 30-40% of women presenting to infertility clinics. Endometrial tissue secretes a number of abnormal cytokines which have been implicated in aberrant ovulation, fertilization and tubal function. Nonetheless, minimal and mild endometriosis have not been definitively proven to cause infertility.
Both medical and surgical techniques have been used to treat endometriosis. Only total abdominal hysterectomy and bilateral salpingo-oophorectomy has resulted in high rates of cure. All other treatments offer high rates of temporary diminution of pain but should be considered suppressive only. Medical treatment is designed to inhibit ovulation and concomitant estrogen secretion because estrogen is "fertilizer" for endometriosis growth. A variety of agents including oral contraceptives, progestins, GnRH agonists and danazol have been employed for this purpose.
Ultimately, except for mechanical restoration of pelvic anatomy, medical and surgical treatment of endometriosis has NOT been shown to increase pregnancy rates. Treatment may theoretically, however, slow the progression to higher stage disease.
Male Factor Infertility
Unfortunately, few cases of male factor reproductive disorders can be remedied. Evaluation for male factor infertility is analogous to that of the female. Attention is paid to the hypothalamic-pituitary-testicular hormonal axis (LH, FSH, testosterone), and to the patency of the spermatic outflow tract (vasogram) and testicular function (testicular biopsy).
Particular abnormalities identified by semen analysis may suggest evaluation for specific presumptive causes of male-factor infertility. For instance, elevated percentages of tapered shaped sperm heads on morphologic examination suggest varicocele. Varicoceles are abnormal dilatations (varices) of scrotal veins. They are commonly found within the left scrotum superior to the testicle and feel like a "bag of worms". They are usually caused by deficient valves in the left internal spermatic vein and are noted in about 40% of men presenting to infertility clinics. Treatment is by ligation of the internal spermatic vein, but such treatment has resulted in only marginal increases in pregnancy rates rendering varicocelectomy controversial.
Occasionally, vas occlusion can be surgically corrected and in cases of hormonal deficiency, replacement hormonal therapy can restore testicular function. Recent technology allows in some instances the aspiration of sperm directly from the epididymis in cases of blockage or absence of the vas deferens. However, the few (usually compromised) spermatozoa obtained are usually subjected to micromanipulation techniques during in vitro fertilization procedures so the wife must become subjected to a procedure as well. Formerly, most cases of severe male factor abnormalities have required consideration of donor sperm, but a dramatic advance has been the widespread utility of a micromanipulation technique called intracytoplasmic sperm injection (ICSI). A single motile sperm can be captured and injected into an oocyte resulting in normal fertilization. Therefore men with extremely low sperm counts and quality can potentially achieve a pregnancy using their own genetic sperm.
Assisted Reproductive Technologies
Sperm and Oocyte Donation- If inadequate gametogenesis is the cause of infertility, couples are offered therapeutic donor insemination, donor oocytes, or both.
In vitro fertilization/embryo transfer - Irreparable tubal disease requires consideration of in vitro fertilization and embryo transfer (IVF-ET). Endogenous gonadotropin release is first down-regulated using a GnRH agonist to prevent interference with the ovulation induction process. Then the ovaries are stimulated to produced maximal numbers of oocyte-containing follicles using hMG. Oocytes are then aspirated transvaginally under ultrasound guidance during an outpatient procedure using local anesthesia. The oocytes are incubated with sperm in vitro. If fertilization occurs, embryos are transferred back into the uterus. Beside tubal disease or absence, IVF-ET has been used for other indications such as male factor infertility, endometriosis and unexplained infertility. Success rates average 20% but some centers are now achieving >35% success rates ("take-home baby rate" per embryo transfer procedure) depending on the age and infertility diagnoses of the candidates.
Zygote Intra-Fallopian Transfer (ZIFT)- Same procedure as IVF except embryos (zygotes) are transferred into the Fallopian tubes rather than the uterus with the rationale that exposure to normal tubal physiology facilitates pregnancy rates. Disadvantages include the need for normal tubes and the need for laparoscopy under general anesthesia for tubal embryo transfer. The ability to fertilize can be ascertained as in IVF.
Gamete Intra-Fallopian Transfer (GIFT)- Same procedure as ZIFT except gametes (instead of embryos) are transferred into the tubes immediately after retrieval of the gametes. This does not allow documentation of the ability of the gametes to fertilize.
Oocyte cryopreservation- Unlike sperm, oocytes are extremely sensitive to cryopreservation and do not survive the process. Once fertilization has occurred, however, about one half of cryopreserved embryos may survive the freeze/thaw process and can be transferred into the uterus.
Gamete micromanipulation- When fertilization proves defective, the oocyte zona pellucida can be mechanically opened via micromanipulation techniques to facilitate sperm entry. Or, a single sperm can be injected directly into the cytoplasm of the oocyte (ICSI, intracytoplasmic sperm injection).
Ultimately, only about 50% of couples who seek help for infertility eventually report a pregnancy. However, amongst the group that does conceive, ectopic pregnancy, miscarriage and perinatal mortality surpass what would be expected in the general population. Therefore, of the original infertile population presenting for treatment, over half will eventually confront biologic childlessness. Many times financial and emotional stresses cause the cessation of infertility treatments even though there may still be efficacious medical treatments available to the couple.
A major responsibility of the physician is to suggest to a couple when to discontinue attempts at conception.
Review of Section III
Each treatment plan must be custom-designed based upon etiology(ies), patient age, resources, desires etc. Note that available treatments are often designed to bypass certain irreparable obstacles in the reproductive system. For example, hMG bypasses hypothalamic/pituitary dysfunction by directly stimulating the ovaries. IVF bypasses tubal and peritoneal disease, and optimizes sperm function. And, artificial insemination bypasses cervical mucus dysfunction.
Understanding the mechanisms of action of the ovulation inducing agents is critical to rationally treat anovulatory women. There are treatments available to circumvent almost all problems with the reproductive system with the following three prerequisites: functional spermatozoa, functional oocytes and a normal uterus. Even these circumstances can be skirted if the couple is willing to use donated gametes and/or surrogacy when necessary.