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CASE 1-PRECONCEPTION CARE #2

KR is a 35 year old women who comes to the office after trying for 1.5 years to become pregnant…

WHAT IS INFERTILITY?

Infertility is the inability to get pregnant after a year of unprotected intercourse.

About 10% of couples in the United States are affected by infertility. Both men and women can be infertile.

According to the American Society for Reproductive Medicine, 1/3 of the time the diagnosis is due to female infertility, 1/3 of the time it is linked to male infertility and the remaining 1/3 is due to a combination of factors from both partners. For approximately 20% of couples the cause can not be determined.

WHAT CAUSES INFERTILITY? Female infertility can be caused by a number of factors,

including the following: Damage to fallopian tubes. Damage to the fallopian tubes

(which carry the eggs from the ovaries to the uterus) can prevent contact between the egg and sperm.

Hormonal causes. Some women have problems with ovulation. This means that synchronized hormonal changes leading to the release of an egg from the ovary and the thickening of the endometrium (lining of the uterus) in preparation for the fertilized egg do not occur. These problems may be detected using basal body temperature charts, ovulation predictor kits, and blood tests to detect hormone levels.

Cervical causes. A small group of women may have a cervical condition in which the sperm cannot pass through the cervical canal. Whether due to abnormal mucus production or a prior cervical surgical procedure, this problem may be treated with intrauterine inseminations.

Unexplained infertility. The cause of infertility in approximately 20% of couples will not be determined using the currently available methods of investigation.

Age-related

AGE AND FERTILITY

The number of infertile couples rises with increasing age. This is because women are born with a finite number of eggs.

Thus, as the reproductive years progress, the number and quality of the eggs diminish. The chances of having a baby decrease by 3% to 5% per year after the age of 30. This reduction in fertility is noted to a much greater extent after age 40.

Polycystic Ovary Syndrome

•The most common hormonal disease among women of reproductive age

•Polycystic ovary syndrome is a disorder involving infrequent or prolonged menstrual periods or excess male hormone (androgen) levels. The ovaries develop numerous small cysts and may fail to release eggs.

Fertility Testing

First Visit•Male factors account for 50% of all infertility cases so it is important to examine both partners for fertility issues.

•The first question regarding female fertility is whether or not ovulation is occuring. Previous testing with a fertility monitor will provide reproductive specialists with valuable information concerning ovulation.

•The first test performed is the measurement of FSH and LH on the third day of the cycle so it is important that the appointment be scheduled on that day.

Fertility Testing

Second Visit•Occurs on the day of the LH surge which is before ovulationin most cases.

•During the first cycle it is common for the following tests to be performed:

•Cervical Mucus Test – This involves a postcoital which determines if the sperm is able to penetrate and survive in the cervical mucus. It also involves a bacterial screening•Ultrasound Test – used to assess the thickness of the lining of the uterus (endometrium), monitor follicle development, and check the condition of the uterus and ovaries. Another ultrasound may be performed 2 or 3 days later to confirm that an egg has been released.

Fertility Testing

•Hormone tests are also performed to assess the levels of hormones that contribute to the reproductive process

•Which hormones are tested?•Luteinizing hormone (LH)•Follicle Stimulating Hormone (FSH)•Estradiol•Progesterone•Prolactin•Free T3•Total Testosterone•Free Testosterone•DHEAs•Androstenedione

Fertility Testing

•If the semen analysis and the previously mentions battery of tests show normal results then additional testing may be done to best fit the specific patient case.

•Additional Tests:•Hysterosalpingogram (HSG): An x-ray of the uterus and fallopian tubes. A blue dye is injected through the cervix into the uterus and fallopian tubes. The dye shows if there is blockage or any other problem.

•Hysteroscopy: Used if the HSG indicates that there may be problems. The hysteroscope is inserted through the cervix into the uterus, which allows the doctor to see any abnormalities, growths, or scarring in the uterus. The hysteroscope takes pictures which may be used for future reference.

Fertility Testing

•Additional Tests:•Laparoscopy: Uses a narrow fiber optic telescope. The laparoscope is inserted through a woman’s abdomen to look at the uterus, fallopian tubes, and ovaries. It is used to checking for endometriosis, scar tissue, or other adhesions.

•Endometrial biopsy: This is a procedure which involves scraping a small amount of tissue from the endometrium just prior to menstruation. This biopsy is performed to assess whether there is a hormonal imbalance or not.

*It is important to determine whether or not the patient is pregnant before performing the above two tests so as not to harm the growing fetus.

FERTILITY DRUGS

Fertility drugs remain the primary treatment for women with ovulation disorders

Some are taken orally and some are injected. In general, these medications work by causing the release of hormones that either trigger ovulation or regulate it.

Most work like natural hormones that are found in the body

CLOMIPHENE (CLOMIDE, SEROPHENE) Mechanism of Action: selective-estrogen receptor-

modulator due to its ability to compete with estradiol for estrogen receptors at the level of the hypothalamus. Clomiphene blocks the normal negative feedback of circulating estradiol on the hypothalamus, preventing estrogen from lowering the output of gonadotropin releasing hormone. During clomiphene therapy, the frequency and amplitude of GnRH pulses increase and stimulate the pituitary gland to release more FSH and LH.

Taken orally to stimulate ovulation in women who have polycystic ovary syndrome or other ovulation disorders

Dosing: 50 mg daily for 5 days. Start on day 5 of menstrual cycle. Test for ovulation with the ovulation monitor.

If no ovulation, increase dose to 100 mg daily for 5 days for the next menstrual cycle.

May repeat up to 6 cycles

MORE ON CLOMIPHENE Effectiveness: Clomiphene will induce ovulation in

80% of appropriately-chosen patients; roughly 40% will become pregnant within 6 cycles of treatment.

Side effects: Usually generally mild but include: Hot flashes, blurred vision, nausea, bloating, and

headache. Can also cause changes in the cervical mucus, which

may make it harder to tell when you're fertile and may inhibit the sperm from entering the uterus.

Like many fertility drugs, Clomiphene can increase the chances of multiple births, although it's less likely to cause the problem than some injectable hormones.

HUMAN MENOPAUSAL GONADOTROPINS

This injected medications are for women who don't ovulate on their own due to the failure of the pituitary gland to stimulate ovulation.

Mechanism of action: Gonadotropins directly stimulate the ovaries. This drug contains both follicle stimulating hormone (FSH) and luteinizing hormone (LH). Both FSH and LH are involved in the regulation of ovarian and testicular function.


Repronex-Intramuscular or subcutaneous dosage

Dosage: Adult females: 75 IU of FSH/LH activity given IM or SC once daily for the first 5 days. Adjust dose by no more than 75—150 IU/day every 2 days depending on patient response. Occasionally, the daily dose may be administered in two divided doses.


Humegon and Pergonal -Intramuscular dosage forms

Dosage: Adult females: 75 IU of FSH/LH activity given IM once daily for 7—12 days as indicated by patient response, followed by hCG one day after the last dose of menotropins. If there is indication of ovulation but no pregnancy, the dose of menotropins in the cycle may be increased after 2 more cycles to 150 IU of FSH/LH activity.

FOLLICLE-STIMULATING HORMONES (FSH)

Mechanism of action: Recombinant follitropin mimics the actions of endogenous FSH. The concentration of FSH is critical for the onset and duration of follicular development, and consequently for the timing and number of follicles reaching maturity. FSH works by stimulating the ovaries to mature egg follicles.


Gonal-F-Follitropin-Subcutaneous dosage Dosage: Adult females: Dosage should be

individualized for each patient. The usual initial dose of the first cycle is 150 IU SC initiated in the early follicular phase normally cycle day 2 or 3 and administered once daily until sufficient follicular development is attained.

Follistim- Subcutaneous dosage Dosage: Adult females: Initially, 150—225 IU

SC once daily for at least the first 5 days. After this, the dose may be adjusted individually based upon the ovarian response.


Bravelle-Urofollitropin-Subcutaneous Dosing Dosage: Adult females: Initially, the

manufacturer recommends 225 IU SC daily for the first 5 days of treatment for those patients who have received GnRH agonist or antagonist pituitary suppression. Adjust subsequent dosing to individual patient response.

HUMAN CHORIONIC GONADOTROPIN

Mechanism of Action: In select females with infertility , human chorionic gonadotropin has actions essentially identical to those of LH. Human chorionic gonadotropin (hCG) also appears to have additional, though minimal FSH activity

Used in combination with clomiphene, hMG and FSH, this drug stimulates the follicle to release its egg.

The use of human chorionic gonadotropin (HCG) at therapeutic doses is generally well tolerated when used as a single agent.


Induction of ovulation in females treated with clomiphene who have an appropriate follicular response but a failure to ovulate:

Intramuscular dosage Dosage: Adult females: 5000—10,000 USP

units of HCG IM as a single dose at the appropriate day, as determined by exam and ultrasound, after the last dose of clomiphene (usually 3—4 days after the last clomiphene dose).


Induction of ovulation following treatment with menotropins or follitropin in females with infertility:

Intramuscular dosage Adult females: 5000—10,000 USP units of HCG IM as a single dose one day after the last dose of menotropins or FSH pre-treatment. The labeling for menotropins recommends an HCG dosage of 10,000 USP units for anovulation.

Subcutaneous dosage (Ovidrel)recombinant- hCG):Adult females: 250 mcg SC as a single dose one day after the last dose of menotropins or FSH pre-treatment.

GONADOTROPIN-RELEASING HORMONE (GN-RH) ANALOGS

This treatment is for women with irregular ovulatory cycles or who ovulate prematurely before the lead follicle is mature enough during hMG treatment. Gn-RH analogs deliver constant Gn-RH to the pituitary gland, which alters hormone production so that a doctor can induce follicle growth with FSH.

GONADOTROPIN-RELEASING HORMONE (GN-RH) ANALOGS

Goserelin acetate -Zoladex

Leuprolide acetate –Lupron

Nafarelin acetate –Synarel

*These have an indication for endometriosis which could be a cause of infertility.

AROMATASE INHIBITORS

Mechanism of action: Normally, through negative feedback, estrogens decrease the release of FSH from the pituitary gland; it is hypothesized that by blocking estradiol production through inhibiting aromatase, letrozole may increase the release of FSH and induce ovulation.

AROMATASE INHIBITORS

Letrozole (Femara)-Oral dosing Dosage:Adult premenopausal females: Limited

studies indicate that 2.5 mg, 5 mg, or 7.5 mg PO once daily for 5 days, typically given on days 3—7 of the menstrual cycle may be effective

Ensure that patients are not pregnant prior to initiating letrozole. Birth defects have been reported in the children of women who were receiving letrozole during pregnancy. Doctors sometimes prescribe letrozole for women who don't ovulate on their own and who haven't responded to treatment with clomiphene citrate. Letrozole is not approved by the Food and Drug Administration for inducing ovulation. The drug's manufacturer has warned doctors not to use the drug for fertility purposes because of possible adverse health effects.

FERTILITY DRUGS AND THE RISK OF MULTIPLE PREGNANCIES

Injectable fertility drugs increase the chance of multiple births. Drugs such as Clomid increase the chance of multiple births but at a much lower rate. The use of these drugs require careful monitoring with blood tests, hormone tests and ultrasound measurement of ovarian follicle size. Generally, the greater the number of fetuses, the higher the risk of premature labor. Babies born prematurely are at increased risk of health and developmental problems.

The risk of multiple pregnancies can be reduced. If a woman requires an HCG injection to trigger ovulation, and ultrasound exams show that too many follicles have developed, she and her doctor can decide to withhold the HCG injection.

Metformin…

• Metformin is a diabetic medication, that is thought to work because polycystic ovary syndrome is associated with insulin resistance

• Studies have shown that there is no advantage when using metformin alone over clomiphene and the combination of metformin and clomiphene was no better than clomiphene alone

Metformin…

In answer to the patients question

•Metformin was an appropriate choice for her friend most likely because she has polycystic ovary syndrome. In this case metformin will help her friend to ovulate on a more regular cycle and increase chance of conception.

•In the patient’s case, we would not recommend metformin to her until she visits with a fertility specialist and her inability to conceive is defined.

WORKS CITED Clinical Pharmacology Epocrates Online www.americanpharmacy.org www.Mayoclinic.com www.Webmed.com

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