DR. RESHEF- EDUCATE ME!
IN THIS PAGE, I WILL HIGHLIGHT COMMON TOPICS IN MY SUBSPECIALTY OF REPRODUCTIVE ENDOCRINOLOGY AND INFERTILITY (REI). YOU MAY CONTACT ME VIA E-MAIL WITH QUESTIONS OR IF YOU WOULD LIKE ME TO ADD TOPICS.
In Vitro Fertilization
Male factor infertility
Menopause (including Hormone Replacement Therapy)
Pre-implantation Genetic Testing (PGT)
Polycystic Ovary Syndrome (PCOS)
Definition: Pregnancy outside the uterine cavity. It is often called tubal pregnancy since the majority is in the fallopian tube.
Incidence: Approximately 2% of all pregnancies. The incidence has been increasing since the 1970’s. It causes 9% of all pregnancy-related maternal deaths.
Causes: Infection of the reproductive organ (pelvic inflammatory disease, PID) is the most common cause. Other factors are prior ectopic pregnancy, smoking, prior tubal surgery, increasing age.
Signs and Symptoms: abdominal pain, abnormal bleeding in pregnancy are the most common symptoms. Abdominal tenderness is the most common sign. Many patients with ectopic pregnancy have no symptoms at all.
Diagnosis: Blood levels of human chorionic gonadotropin (HCG) and progesterone combined with vaginal ultrasound. When the HCG level is above 1500, if a gestational sac is not seen by ultrasound, an ectopic pregnancy must be presumed. Very low progesterone levels may indicate ectopic pregnancy, especially if HCG levels do not rise appropriately.
Treatment: Medical, surgical, or expectant management. Medical treatment with methotrexate (MTX), a chemotherapy drug, may be offered for an unruptured ectopic <3.5 cm in diameter by ultrasound in a medically stable healthy patient who desires future fertility and can be followed reliably. Surgical treatment, usually by outpatient laparoscopy, may include removal of the ectopic as well as the fallopian tube, or conservative removal of the ectopic alone with preservation of the tube. The success rate of medical treatment (when given appropriately) is 67-100%. Most medical treatments require a single intramuscular injection of MTX. Expectant management, in which the patient is followed closely without medical or surgical intervention, is appropriate when the patient is relatively asymptomatic and stable and her HCG levels are declining.
Definition: A condition in which tissue that resembles the lining of the uterus (endometrium) is found outside the uterus. While the most common locations for the lesions are behind the uterus (cul-de-sac), on the ovaries, or on the bladder surface, lesions have been found in the bowel, appendix, c-section scars, lungs, and even the eye.
Incidence: In the general population, 7-10% of women have endometriosis. In infertile women, 20-50% have this condition. The incidence of endometriosis has not been increasing. This condition can occur in any woman regardless of race. First-degree relatives of women with endometriosis have 10-fold increased chance of developing the condition.
Causes: Cells from the cavity of the uterus commonly are found in the abdominal cavity during menstruation (retrograde menstruation). In some women, perhaps because of inability of the immune system to reject such cells, they will implant and grow. Other theories of endometriosis include change of normal cells inside the abdomen to endometrial cells under unsusual stimulation, and spread of cells from inside the uterus through blood vessels to distant areas.
Signs and Symptoms: Many patients with endometriosis have no symptoms. The severity of symptoms does not correlate with the severity of endometriosis. Painful periods (dysmenorrhea), painful intercourse (dyspareunia), infertility, and irregular periods are the most common symptoms. Tenderness during a pelvic examination and the presence of nodules or cysts are typical signs though not very common overall.
Diagnosis: Direct visualization of the condition confirmed by biopsy (if the surgeon is uncertain about the lesions) is the standard for diagnosis of endometriosis. This is usually done by laparoscopy as an outpatient. Physical examination and history are very unreliable and should not be used to establish the diagnosis. Imaging procedures such as ultrasound or MRI may be suggestive but not diagnostic. The severity of endometriosis is classified in 4 stages (minimal, mild, moderate, severe) based on visual criteria at surgery.
Treatment: Options include no treatment, medical treatment, or surgical treatment. No treatment is an appropriate option when endometriosis was diagnosed already and/or previously treated, and the patient is asymptomatic. Medical treatment includes birth control pills, progestin (e.g. norethindrone), danazol (rarely used due to side effects), or GnRH-agonists (e.g. Depo-Lupron). Surgical options include laparoscopic treatment (by laser or non-laser instruments) as an outpatient; by laparotomy (larger abdominal incision, usually requiring a short hospitalization- an uncommon practice nowadays); or a hysterectomy, with or without removal of ovaries. Treatment must take into account the patient’s wishes for future fertility; the severity of her symptoms and the resulting disability from symptoms; previous treatments and treatment failures; and side effects and tolerance of medications. FIRST DO NO HARM should be the motto for the doctor treating endometriosis and also what the patient should keep in mind when considering treatment options.
Endometriosis and Infertility:
Infertility patients have an increased prevalence of endometriosis. Patients with endometriosis are more likely to be infertile. The greater the extent of endometriosis, the lesser the likelihood of pregnancy. Medical or surgical treatment of endometriosis often improves fertility. How does endometriosis contribute to infertility? In cases of significant amount of endometriosis, scar tissue involving the tubes or ovaries may interfere with the normal mechanism of egg capture by the fallopian tubes following ovulation. Another possible mechanism contributing to infertility is the various inflammatory substances released in response to endometriosis lesions that may interfere with ovulation and sperm function.
Surgical treatment of endometriosis, now mostly accomplished by outpatient laparoscopy, may generally improve fertility by 25%. Treatment of low grades of endometriosis (minimal or mild) by surgery results in only modest amount of increase in fertility. Nevertheless, if laparoscopy is performed for diagnostic purposes, it is advisable to treat endometriosis even if it is limited. In vitro fertilization (IVF) should be considered for infertile patients with significant amounts of endometriosis (moderate or severe). While severe endometriosis may be associated with some reduction in egg quality, especially if present on the ovaries (endometriomas), IVF still offers greater chance of pregnancy to patients with severe disease compared with other infertility treatments. Care must be taken when surgically treating ovarian endometriosis (endometriomas), since overly aggressive treatment may result in reduction in blood supply to the ovary and reduction in ovarian response.
Definition: Tissue growth originating from the muscle of the uterus. Tumors of the uterine muscle. Also known as leiomyomas, myomas.
Incidence: Fibroids are common, occurring in at least one third of all women. They are the most common solid pelvic tumors in women and the leading indication for hysterectomy. They become more common in older women. They are more common in certain ethnic groups (Africans and African-Americans). They are more common in women whose mothers had fibroids.
Causes: It is yet unclear as to why normal uterine muscle may develop fibroids. While fibroids are tumors, they are rarely malignant. Certain conditions may contribute to growth or shrinkage of fibroids. Excess estrogen or progesterone may stimulate growth of fibroids (e.g. in pregnancy or obesity or in women taking estrogen or certain oral contraceptives). Menopause or drugs that cause reduction of these hormones may cause shrinkage.
Signs and Symptoms: Most fibroids are asymptomatic. The most common symptoms are the result of growth and pressure on adjacent tissue (abdominal and pelvic pain, bladder symptoms, bowel symptoms) or instability of the uterine lining (irregular or excessive vaginal bleeding).
Diagnosis: Pelvic examination may discover enlargement of the uterus or irregular shape but may miss smaller fibroids, especially deep in the uterine muscle. Ultrasound (vaginal and/or abdominal) is the most common diagnostic tool. MRI or CT-scan may be used in case of very large fibroids or if there is a question of whether the tumor arises from the uterus or ovary.
Treatment: Most fibroids do not require treatment. Only if symptoms become disruptive to the woman’s quality of life or if the fibroids may cause infertility should treatment be offered. Patients with fibroids who have few or no symptoms should be examined closely at regular intervals to detect change in fibroid size. Treatment plans should take the severity of symptoms, patient’s age, and patient’s reproductive goals into consideration. If no conception is ever desired, hysterectomy or uterine artery embolization (UAE, deliberate blockage of the blood supply to the fibroids) or ultrasound ablation of the fibroids under MRI guidance may be offered. Surgical removal of fibroids without removing the uterus (myomectomy) may be offered to women who have bothersome symptoms or those wishing to get pregnant or those not wishing a hysterectomy. Myomectomy may be performed by laparoscopy or hysteroscopy under special circumstances. Large fibroids or fibroids deep in the uterine muscle usually are removed by laparotomy (abdominal procedure with incision similar to C-section). Laparoscopic robotic treatment of fibroids may only be performed by surgeons with superior expertise in this technique. UAE or ultrasound treatment of fibroids should not be offered to women who are attempting to get pregnant or plan on being pregnant in the future since these procedures may compromise blood supply to the ovaries and ovarian function. Treatment of fibroids with medications may be effective but only on a temporary basis. GnRH agonists such as leuprolide (Lupron) may be used to shrink fibroids prior to surgical treatment. This treatment by itself may not cure fibroids, which may grow back after discontinuing the medication.
Definition: Inability to get pregnant after one year of attempts (if the woman partner is under age 35) or after 6 months of attempts (if over age 35).
Incidence: Approximately 10-12% of couples are unable to conceive. The chance of a fertile couple to conceive is 20-25% each month, or 85% after 12 months of attempts.
Causes: Roughly one third of infertility is due to male factors, one half due to female factors, and the remainder either due to combined factors or unexplained infertility. Among female factors, the most common causes are the peritoneal factor (tubal damage, scar tissue, and/or endometriosis) and problems with ovulation. A distant third factor is cervical mucus abnormalities. Infection, mostly sexually transmitted, causing tubal damage in the female and scarring in the male is a common cause. Environmental factors such as exposure to toxins is emerging as an increasingly important factor of infertility, especially in the male.
Diagnosis: In the male, the semen analysis (preferably using strict morphology criteria) is the mainstay of diagnosis. A urologist specializing in male infertility is often the preferred physician to refer to for evaluation and treatment. In the female, testing tubal and uterine integrity via hysterosalpingogram (HSG) or sonohysterogram (SHSG) is the preliminary basic workup for the peritoneal factor, followed by a laparoscopy to diagnose and treat pelvic scarring, tubal blockage, or endometriosis. Ovulation can be determined by the basal body temperature (BBT) chart, urine ovulation test, and/or a well-timed blood level of progesterone (luteal progesterone). While the utility of the post-coital test (PCT or PK) is debated, it may be helpful in directing the physician to additional tests. Blood tests for hormone levels should be performed only when indicated by certain signs and symptoms (e.g. irregular periods, breat discharge). Testing of basic immune functions is only indicated in the case of habitual miscarriages.
Treatment: male factor infertility may be treated by reducing adverse environmental factors (smoking, alcohol, stress, excess heat, certain offensive medications); beneficial medications (e.g. antibiotics, clomiphene), inseminations, or in vitro fertilization (IVF). Female peritoneal factors may be addressed at surgery (usually at outpatient laparoscopy) or bypassed by performing IVF. Ovulation problems may be addressed by changing life habits (weight loss, stress reduction); fertility medications (either pills- clomiphene or letrozole, or injections of gonagotropins). Metformin, a medication for diabetes, may be used for correction of ovulatory problems in insulin-resistant patients. Cervical mucus abnormalities may be addressed by treatment with antibiotics or bypassed by artificial insemination. For long-standing infertility resistant to conventional treatment, IVF is offered. Generally, treatment of infertility must take into account the patient’s age, anxiety level, financial ability, length of infertility, and what was already done in the past for this condition. The principle FIRST DO NO HARM must be kept in mind at all times.
Definition: The placement of sperm in the reproductive organs for conception. Placement of sperm directly into the uterine cavity is called intra-uterine insemination (IUI). Placement of the sperm into the cervix (mouth of the uterus) is called intra-cervical insemination (ICI). Intra-vaginal insemination (IVI) is placement of sperm into the vagina. Both ICI and IVI are rarely performed. The following discussion will deal primarily with IUI. IUI can be performed with either husband’s (or partner’s) sperm, or with donor sperm. Placement of sperm into the fallopian tubes (ITI) is rarely done nowadays.
Indications: IUI is performed when the sperm is unable to swim through the cervical mucus (cervical factor infertility); when the sperm is deficient (low count, low motility, poor shape); when a couple can not perform intercourse for physical or psychological reasons; and for unexplained infertility. Most donor inseminations in the physician’s office are done by IUI.
Procedure: The physical part of the IUI is well-tolerated by the patient. The sperm is processed in the laboratory (by “sperm wash” or other methods), concentrated in low volume, then placed into the uterus by the health care practitioner via a thin plastic tube (catheter). The sperm is placed into the middle of the uterine cavity. The patient usually rests for 5-15 minutes, then may return to normal activities with few restrictions. Other than a menstrual-like mild cramp during sperm insertion, most patients tolerate IUI well. No pain medications are needed. IUI normally takes a few seconds. The sperm specimen is processed in the laboratory normally by several rounds of centrifugation, intended to separate the sperm portion from the seminal fluid. This allows the laboratory personnel to place the sperm in a small volume of culture fluid, both to rid the sperm specimen of seminal fluid (which contains certain substances that may cause uterine cramping), and to reduce the chance of “spill-over” from the small uterine cavity.
Success rate: Pregnancy rates from IUI vary widely, depending on the indication for IUI and the quality of sperm. The “yard stick” for success rate per month is the normal success rate for a fertile couple of 20-25% per month. Regardless of the quality of sperm or additional fertility medications (clomiphene, letrozole, injectable medications), the success rate of IUI will not exceed this rate. Generally, IUI has 5-20% chance of success each month, which may necessitate repeating the process several times to give the patient a reasonable chance of conception. In the case of very poor sperm quality or other severe infertility factors (severe endometriosis, severe scar tissue or tubal disease, advanced patient age), the practitioner should limit IUI attempts to 3-6 and promptly discuss IVF as an option.
Complications: Infection from IUI is very rare. Discomfort is usually minimal. Perhaps the most common “complication” is performing IUI too many times without adequately evaluating the patient or without offering more effective alternatives.
IN VITRO FERTILIZATION
Definition: In vitro fertilization (IVF) literally means “fertilization in the glass” or “fertilization in the laboratory”. The term denotes a procedure in which sperm and eggs are placed in a dish in the laboratory, then transferred to the uterus after fertilization and further development (embryo transfer). IVF falls under the umbrella of Assisted Reproductive Technology (ART), which also includes assisted hatching (AH), intracytoplasmic sperm injection (ICSI), and embryo and sperm freezing and storage (cryopreservation)..
History: The first live birth from IVF occurred in England in 1978. The first IVF birth in the U.S. occurred in 1981. The first birth from IVF/ICSI occurred in Belgium in 1992. Freezing of eggs and pre-implantation screening and diagnosis (PGS, PGD) are recent additions to ART, even though still experimental or else with uncertain benefits.
Indications: While IVF originally was designed to help bypass the fallopian tubes in case of tubal damage or absence, it is now most commonly performed in couples with severe male factor, endometriosis, pelvic adhesions (scar tissue), or unexplained infertility.
Procedure: In IVF, the goal is to retrieve several eggs in order to select the best 1-3 embryos for transfer. First, the ovaries are suppressed with birth control pills and/or Lupron daily injections. The goal is to have eggs of similar maturity when the ovaries are then stimulated with injectable hormones. After approximately one week of ovarian stimulation, the eggs are removed from the ovaries (egg retrieval) under IV sedation and under ultrasound guidance. Three to five days later, embryos will be placed in the uterine cavity (embryo transfer). Two weeks later, a pregnancy test will be performed. The most common IVF protocol lasts approximately 7 weeks, of which 5 weeks are for ovarian suppression, one week for ovarian stimulation, and one week for egg retrieval and embryo transfer.
Success Rates: When IVF was introduced in the early 1980’s, live birth per procedure rate of 10% was considered reasonable. According to the Society for Assisted Reproductive Technology (SART, www.sart.org), the live birth per cycle start (intended retrieval) in for women under age 35 using their own eggs is 40-50%. You may find the success rate for various IVF procedures based on age groups for each IVF program on www.sart.org or www.cdc.gov.
Complications: Long-term health complications from IVF are rare for the patient. After more than 40 years of IVF, we do not see an increase in cancer or other illnesses. Most of the adverse effects are in the babies, usually as a consequence of prematurity. Multiple births, especially triplets and above, are now rare.
MALE FACTOR INFERTILITY
Definition: The inability to get pregnant after 12 months of conception attempts (if the female partner is under age 35) or 6 months (if the female partner is over age 35) due to problems with the male partner.
Epidemiology: Approximately 20% of all infertility is due to male factors alone and in an additional 30-40% of infertility there are sperm problems in addition to female factors. Male factor infertility is more common in environmentally compromised areas (pollution, water contaminants, pesticides, herbicides). Recent population studies show that sperm counts have been declining universally even though infertility has not been increasing appreciably.
Causes of Male Factor Infertility: In at least 50% of male-factor infertility, no causes can be identified. The remainder 50% of causes can be divided into 2 major categories: environmental and genetic (acquired and congenital).
Environmental or acquired causes:
– Excess heat (occupational, e.g. truck drivers, state troopers, welders, firefighters; habits, e.g. excess use of hot tub, tub baths, tight cloths, jockey underwear [controversial])
– Drugs (certain antibiotics, anabolic steroids, testosterone, tobacco, marijuana, alcohol)
– Toxins (pesticides, herbicides, heavy metals, lead, mercury, paint, paint thinner)
– Stress (including erectile dysfunction)
– Excess exercise, including bicycling
– Chronic disease (e.g. anemia, malnutrition, cancer, neurological disease, diabetes, obesity)
– Dietary deficiencies (e.g. zinc, vitamin C, folic acid)
– Varicocele (enlarged veins in the scrotum)
– Diseases of the male genital tract (infection, cancer, trauma, retrograde ejaculation)
– Surgery on the male genital tract (e.g. undescended testicle, hernia)
Genetic and other congenital causes:
– Y-chromosome abnormalities
– Other chromosome abnormalities (e.g.Klinefelter’s XXY)
– Hormonal abnormalities (diabetes, high prolactin, thyroid abnormalities, adrenal abnormalities, pituitary and hypothalamic abnormalities
Diagnosis: History and physical examination are essential. The semen analysis is the single most important diagnostic test for male infertility. Hormonal evaluation (FSH, LH, thyroid, testosterone, prolactin) should be offered in case problems with sperm count, motility, or morphology cannot be readily explained. At present, most advanced infertility practices offer a semen analysis with strict sperm shape criteria (Kruger’s, Tygerberg) that are more predictive of sperm dysfunction than the conventional WHO criteria offered by non-specialty laboratories.
– Avoidance of damaging environmental factors (smoking, heat exposure, heavy exercise, toxins, certain drugs)
– Stress reduction
– Medications: antibiotics (if infection suspected); fertility medications (including clomiphene or Human Chorionic Gonadotropin (HCG) or LH/FSH by injections)
– Vitamins (questionable): Folic acid, zinc, L-carnitine)
– Alternative Medicine (e.g. herbs, acupuncture- questionable but generally not harmful)
– Surgery (e.g. varicocele repair, vasectomy reversal)
– In vitro fertilization (typically with Intracytoplasmic Sperm Injection, ICSI; if indicated, with sperm extraction from the epididymis or testicle
MALE FACTOR INFERTILITY
THINGS TO AVOID:
Medications (testosterone, sulfa, nitrofurantoin, steroids, valproic acid, spironolactone, allopurinol, lithium, certain anti-depressants, certain anti-psychotics)
Excess heat (but debate about boxers vs. briefs is yet unresolved…)
Chemicals (pesticides, herbicides, strong solvents, oil-based paints, heavy metals)
Lubricants (especially K-Y jel, vaseline)
THINGS TO CONSIDER ADDING:
Folic Acid (1.0 mg/day)
Zinc (60 mg/day)
Questionable but not harmful: Vitamins C and E; glutathione; acetyl cysteine, one multivitamin daily
Questionable and potentially harmful: CertainChinese herbs
MENOPAUSE: Cessation of menstrual periods, signifying the end of reproductive ovarian function (Menos= “month” or “monthly” (Greek); Pause= “end of…”). Menopuase by definition starts 12 months after the last period occurred. The average age of menopause is 50-51 years, with a range of 40-58 years.
PERIMENOPAUSE: A period of time before menopause where ovarian function becomes irregular and less predictable. It lasts 2-5 years, at which time menstrual periods become irregular and unpredictable, and symptoms such as hot flashes, sleep disturbance, and vaginal dryness appear.
POSTMENOPAUSE: The period of time after menopause.
The average life expectancy of the American woman is 83 years. Since the average age of menopause is 50-51, a woman in the U.S. will spend more than a third of her life after menopause. In 1900, the life expectancy was 49 years and the average age of menopause was similar to today, Therefore, relatively few women experienced menopause then. While in 1900 there were only 3 million Americans older than 65, the projected number for 2030 is 57 million, or 17% of the total population. It is obvious that menopausal health issues in women are and will be even more so a major part of health care concerns in the U.S.
Menopause is a natural process whereby the ovaries stop producing eggs for reproduction, and the production of ovarian hormones significantly decreases. The vast majority of cases of menopause, then, are natural and inevitable. “Surgical menopause” occurs when the ovaries are removed prior to natural menopause. If menopause occurs prior to age 40, it is considered “premature menopause”. Most premature menopause cases do not have an explainable cause. Some may be caused by chemotherapy or radiation for cancer. Some may be caused by auto-immune factors or by problems with chromosomes. Smoking is the major recognizable environmental factor that may bring menopause early. Early menopause in the mother is often associated with early menopause in her daughters. A woman is born with a certain number of eggs in her ovaries, a number which diminishes gradually throughout her reproductive life until it is completely depleted by menopause. With the gradual depletion of eggs, especially during perimenopause, reproductive ovarian hormones such as estrogen and progesterone are decreased as well, resulting in irregular periods and some of the typical physical symptoms of menopause.
Signs and Symptoms:
Hot flushes (vasomotor flushes) are the hallmark of menopausal and perimenopausal symptoms. In the perimenopause, as many as 25% of women report hot flushes. At least 50% of women will report it after the onset of menopause, but the incidence declines to 20% 4 years after menopause. Most women will have hot flashes for 1-2 years, but 25% will have them for longer than 5 years. Nightly hot flushes causing sleep disturbances (“night sweats”) are also common but transitory. Vaginal dryness (atrophic changes) is also common after menopause, indicating prolonged estrogen deprivation. It may be associated with vaginal irritation, frequent vaginal and urinary tract infections, and discomfort during intercourse (dyspareunia). Bladder and rectal relaxation (drop), with or without symptoms, are also common as a result of estrogen deprivation. Psychological or psychiatric disorders are not a consequence of menopause, though their incidence increases with age. Depression, actually, is less common among middle-aged women. Poor sleep patterns due to estrogen deprivation may lead to temporary disruption of emotional stability, as is the case with sleep deprivation at any age. Dementia and Alzheimer’s disease are not caused by menopausal estrogen deprivation.
The diagnosis of menopause is based on clinical symptoms- lack of menstrual periods for 12 months at the appropriate age (over 40). Other causes of lack of periods (amenorrhea), such as pregnancy, thyroid problems, stress, eating disorders, or chronic lack of ovulation (especially in PCOS) must be ruled out. Blood test for the hormone FSH may support the correct diagnosis.
Once again, the principle of FIRST DO NO HARM must be kept in mind prominently when treatment of menopause is considered. Menopause often does not require any treatment. It should be treated if there are troublesome side effects that directly interfere with normal, every day function, or to prevent bone loss (osteoporosis, osteopenia) that may lead to hip or vertebral fractures and disability. Diet rich in plant-derived estrogens and weight-bearing exercises should be advocated to most post-menopausal women. Increase in calcium intake, especially in those that can not tolerate dairy products, should be considered (1200-1500mg calcium per day). For hot flushes, diet, exercise, certain breathing exercises, and plant-derived estrogens (e.g. isoflavones from soy products) or Black Cohosh should be attempted first. Estrogen or estrogen-progestin therapy is the next line of treatment. It should be given in the smallest effective dose for the shortest duration (usually less than 5 years) to patients without contraindications to such therapy. Contraindications include certain cancers, blood clots, or significant cardiovascular disease or risks. “Natural Hormone Therapy” or “Bio-Identical Hormone Therapy” is a misleading catchphrase for a class of hormones that are no more natural, no more effective, and no less risky than the commercially-available hormone treatment. Because “bio-identicals” have not been studied as extensively, they must not be given to patients who have contraindications to hormone replacement therapy. If bone health is the only concern, non-hormonal treatment with bone-conserving medications may be offered.
The following constitute menstrual abnormalities: Lack of menstrual periods; periods with interval longer than 35 days or shorter than 21 days; periods with bleeding greater than 7 days; bleeding or spotting in-between periods.
Abnormal menstrual periods are very common, especially in the first 1-2 years after the start of the menstrual cycles; after delivery of a baby or a miscarriage; and in the years before menopause (usually ages 40-50). Most women have at least several instances of abnormal bleeding during their reproductive life.
Most abnormal periods are due to benign conditions such as pregnancy, lack or infrequent ovulation, non-malignant growths in the cavity of the uterus (polyps, fibroids), or hormonal irregularities (caused by stress, eating disorders, excess exercise). Less common causes include chromosomal abnormalities, cancer (of the cervix, uterine cavity, fallopian tubes, or ovaries), or blood clotting disorders. Often, no clear cause for a menstrual irregularity can be identified.
A detailed history is very important. History of eating disorders (anorexia or bulimia), excess exercise (e.g. in marathoners, ice skaters, gymnasts), excess stress, breast discharge, or pelvic pain is often indicative of some of the common causes. Physical examination can show problems with the vagina, cervix (mouth of the uterus), enlarged or irregular uterus (fibroids, pregnancy), thyroid gland enlargement, or breast discharge. The ultrasound may be used to diagnose uterine polyps, fibroids, pregnancy, or ovarian cysts, all of which are commonly associated with irregular bleeding. Blood work should only be performed if there are clinical clues to support certain disorders. A sensitive pregnancy test is always welcome, even if history is not supportive of pregnancy. Thyroid tests and prolactin should be performed often. If PCOS is suspected, one may check testosterone, DHEAS, and FSH/LH levels. If perimenopause is suspected, blood FSH level is indicated. Chromosome tests should only be performed in cases of no periods by age 16 or if no other test results are helpful and the patient is under age 30.
Three major categories of treatment: medical, surgical, and no treatment (hands off…)
No treatment: In many instances, abnormal bleeding is temporary. Reassurance without medical or surgical intervention, once a serious disorder (such as cancer or tubal pregnancy) is ruled out, is preferred.
Medical treatment: lifestyle changes may sometimes be the only treatment needed. This includes weight loss for the overweight; weight gain for the underweight; stress reduction for the overly-stressed; correcting eating disorders; and reduction of physical activity for the vigorous exerciser. Correction of abnormal bleeding due to lack of ovulation may be accomplished with birth control pills, progestin pills, or fertility medications. Thyroid medications or medications to reduce excess prolactin may be all the patient need sometimes.
Surgical treatment: removal of abnormal lesions such as fibroids or polyps may be accomplished as an outpatient (laparoscopy, hysteroscopy) or as an inpatient (myomectomy by laparotomy). Endometrial ablation is performed as an outpatient as well. Hysterectomy should only be performed as a last resort for very specific indications, or if less aggressive medical or surgucal treatments are not effective.
Pre-implantation Genetic Testing (PGT)
PGT require IVF, a process in which eggs and sperm are place in the lab (“in vitro”). Following fertilization and development of embryos (fertilized eggs) for 5 days, the embryos, now known as blastocysts, are biopsied and then frozen. The cells from the embryos are then analyzed for genetic abnormalities (PGT). At a future date, only healthy embryos are transferred into the uterus.
PGT is indicated in the following circumstances:
- Patients age 35 or older
- Patients with history of two or more miscarriages
- Patients who had two or more failed IVF procedures (fresh or frozen)
- Patients with a male partner with severe sperm abnormalities Patients who are affected or are carrier of serious genetic disease
POLYCYSTIC OVARY SYNDROME (POCS)
Definition: “Poly” means “many” (Greek). “Cyst“- a fluid-filled area. “Syndrome“- a distinct group of signs and symptoms. PCOS means “many cysts on the ovary, along with certain symptoms”. It is a condition in women which is defined as having two of three characteristics: chronic anovulation (long-term lack of ovulation); chronic hyperandrogenism (excess male hormone); or many cysts on the ovaries by ultrasound.
PCOS affects 5% of all reproductive-age women. Of women who have excess hair, 70% have PCOS. Women with PCOS are commonly obese (40-60%); have excess hair (60-90%); have ovulation problems (50-90%); or are infertile (55-75%).
The diagnosis of PCOS is clinical, meaning that it can be made simply from symptoms and signs rather than from laboratory or imaging studies. The demonstration of polycystic ovaries on ultrasound is not required for diagnosis. Likewise, blood work is not diagnostic of PCOS. It may only be helpful in diagnosing insulin-resistance or diabetes, which are common in patients with PCOS. Excess male hormone is suspected if the patient has excess hair, oily skin, or acne. In most of these patients, however, blood levels of testosterone and other male hormones are normal and therefore not helpful or necessary for diagnosis. A woman with menstrual irregularities (including no periods) who has excess hair in all likelihood has PCOS. While there are other conditions that include these symptoms (e.g. Cushing’s syndrome, congenital adrenal hyperplasia), they are far less common than PCOS. A woman with menstrual irregularities with a unique ultrasound appearance of polycystic ovaries (“string of pearls”) probably has PCOS, even without excess hair.
It is vital for patients and physicians alike to realize that PCOS can not be cured but is readily treatable, and that PCOS is a general metabolic disease, not just restricted to reproductive function. Preventive health care, therefore, is even more important than just treating infertility or menstrual irregularities. Diabetes, heart disease, and certain cancers are more common in PCOS than in the general population. Lifestyle changes and close medical follow-up must therefore be emphasized. Weight loss and restriction of calories are essential in obese PCOS patients. Annual checks for diabetes and thyroid disease are appropriate, especially in PCOS patients with family history of these conditions. The obese patient with PCOS and infertility must be apprised of her increased complication rate in pregnancy. There is an increase in high blood pressure and diabetes in pregnancy as well as delivery complications (greater risk of c-sections and difficult vaginal delivery). It is therefore important to emphasize to the obese, infertile PCOS patient to improve her general health (including weight loss) before and during attempting conception. Such patient should receive special attention from her physician, since there are often sensitive psycho-social issues that must also be addressed. If the goal is to conceive, metformin may be used, either by itself or with oral ovulation medications such as clomiphene or letrozole. Outpatient surgery to cauterize the ovaries may be offered. Injections of gonadotropins or in vitro fertilization are also an option. If the goal is to regulate menstrual cycles, oral contraceptives or progestin pills may be used. If the goal is to decrease excess hair growth, oral contraceptives and/or spironolactone (a diuretic) may be used in conjunction with hair removal measures (laser, shaving, plucking, creams, etc). Most medications to reduce excess hair should not be used in a patient attempting to conceive.
RECURRENT PREGNANCY LOSSES (RPL)
Recurrent pregnancy losses (RPL) is the miscarriage of two or more consecutive pregnancies in the first 20 weeks of pregnancy.
Less than 5% of women will experience two consecutive pregnancy losses and less than 1% will experince three or more. Miscarriges are very common, however, occuring in approximately 25% of all pregnancies.
In 50-75% of couples with RPL, no explanation for the losses can be found. The most common cause for miscarriages is random (non-inherited) chromosomal abnormalities. While chromosomal abnormalities in the husband or wife are uncommon as a cause (less than 5% of RPL), at least 50% of miscarriages are due to a chromosomal abnormalities in the fetus. Some of these may not be identified by routine testing after a miscarriage. Progesterone deficiency is a minor cause of RPL and is very controversial as a cause of miscarriages. Most failed pregnancies have low progesterone due to placental failure when the fetus is abnormal, rather than the reverse, i.e. failed pregnancy due to low progesterone. Abnormalities of the uterus may be found in 10-15% of women with RPL. Metabolic abnormalities such as diabetes or PCOS may increase miscarriages. Approximately 3-15% of RPL are due to immune system abnormalities such as the anti-phospholipid syndrome, in which either the lupus anticoagulant or antiphospholipid antibodies are abnormal.
The evaluation of a couple with RPL may start after 2 consecutive miscarriages rather than waiting for a third miscarriage to satisfy the true definition of RPL. The anxiety and grief that often follows pregnancy losses may necessitate an early investigation of causes. After 2 miscarriages, a possible cause can be identified in 30% of couples. After 3 miscarriages, 40-50% of the time the cause can be identified with the appropriate studies. History-taking must establish that the pregnancy losses were indeed miscarriages rather than tubal pregnancies. Family history of RPL may point to genetic, immune, or uterine factors. While environmental toxins are rarely a cause of miscarriage, the couple should be questioned about toxins (herbicides, pesticides, strong solvents), smoking, caffeine, alcohol, illicit drugs, and medications. Physical examination must include a pelvic examination to rule out birth defects of the vagina and uterus or fibroids. Abnormalities of the uterus are best investigated by ultrasound, HSG (x-ray of the uterus and tubes), or (uncommonly) by CT-scan or MRI. Blood work is usually not helpful in establishing the cause of RPL but the basic blood work may include blood sugar, thyroid tests, and anticardiolipin antibodies and lupus anti-coagulant tests. Testing the couple for chromosomes and testing for blood clotting problems (thrombophilia) may be offered if the preliminary work-up is negative. Tests with no proven benefit include cultures for bacteria or viruses, tests for insulin resistance, antinuclear antibodies, anti-thyroid antibodies, embryotoxic factors and natural killer cells.
The most important issue that must be relayed to the couple with RPL is that their chance of having a successful next pregnancy, even without treatment, is 60-70%. Such reassurance may prevent expensive and unnecessary diagnostic tests and treatments. Lifestyle changes such as smoking cessation, stress reduction, reduction of caffeine and alcohol, and weight reduction should be adopted by the couple. Counseling may help the couple deal with stress and grief. Treatments without benefit include white blood cell immunization and IVIG therapy. Sheer desparation and access to questionable Internet advise may lead the couple to expensive, unproven, and often hazardous treatments. Every reproductive endocrinologist can recount stories of desperate couples who resort to questionable therapies and become incensed with their own “conservative” physician who resists such therapies. Such physician, as caring as knowledgable as he or she may be, is often seen by the Internet-savvy couple as out-of-step with new therapies. Any physician who truly believes in the FIRST DO NO HARM principle, however, must keep the patient’s welfare in mind when dealing with RPL, and only use proven and safe treatments, including NO TREATMENT. Progesterone supplementation may not help but may not be harmful either. One should avoid oral progesterone therapy, however, because of high incidence of side effects and low efficacy. Baby aspirin in case of mild blood clotting abnormality may be helpful. The use of heparin should only be offered to women with true immune and/or blood clotting abnormality. Using a blood-thinner such as heparin is dangerous, especially for very questionable indications. Outpatient surgery to correct abnormalities of the uterus (hysteroscopy and laparoscopy for uterine septum, fibroids, uterine scar tissue) is often very effective in curing RPL.
UNEXPLAINED INFERTILITY (UI)
Definition: Infertility for which no cause can be identified.
Epidemiology: Up to 30% of infertility cases do not have an explanation.
Causes: Factors that cannot be detected by standard infertility tests include failure of implantation, genetic abnormalities in the embryo, immune issues, subtle sperm function abnormalities, and reduction in ovarian function. Tests for these causes are either non-standard, unproven, or non-existent. Even with more sophisticated tests, infertility may not have an apparent cause.
Diagnosis: The diagnosis of unexplained infertility (UI) can only be made after the basic infertility evaluation fails to reveal an obvious abnormality. Therefore, only if the fallopian tubes are open, the semen analysis is normal, the cervical mucus does not impede sperm function, ovulation occurs normally, and peritoneal factors (endometriosis, scar tissue) are absent, the diagnosis can be made. The basic tests for infertility include a semen analysis, hysterosalpingogram (test for the fallopian tubes), confirmation of ovulation, post-coital test (controversial), and a laparoscopy.
Treatment: By default, the treatment of unexplained infertility is by trial and error (empiric).
– Any treatment for UI, except in vitro fertilization (IVF) will not increase the
likelihood of pregnancy more than the regular monthly conception rate of a fertile
– Expectant management: while the monthly pregnancy rate of a patient with UI is lower than the general population, it is appropriate to offer no specific therapy to a young patient who does not wish or cannot afford infertility treatment.
– Intrauterine insemination (IUI): with or without oral fertility medications (clomiphene or letrozole) or fertility injections, IUI appears to improve fertility in UI patients compared with intercourse.
– Oral fertility medications (clomiphene, letrozole): A modest increase in pregnancy rates occurs with empiric treatment of patients with UI. Such treatment should not be offered for more than 3-6 months since it is unlikely to result in a pregnancy with additional treatment cycles.
– Injectable fertility medications (gonadotropins): a modest increase in pregnancy rates occurs with this treatment but it is very expensive and entails increased risks of multiple births and ovarian hyperstimulation syndrome.
– In vitro fertilization (IVF): Perhaps the most successful treatment for UI but clearly the most expensive of all other treatment options. Opinions vary as to the success rate per treatment cycle, and the results vary between IVF programs and depend also on age and other factors. This option should be offered when less aggressive and expensive options fail.
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