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Threatened abortion
- 1. MANAGEMENT OF THREATENED ABORTION Dr. Bushra Hasan Khan JR-1 Department of Pharmacology JNMC, AMU, Aligarh.
- 2. Threatened Abortion A clinical entity where the process of abortion has started, but has not progressed to a state where recovery is impossible. The clinical diagnosis of threatened abortion is presumed when a bloody vaginal discharge appears through a closed cervical os during the first half of pregnancy.
- 3. Threatened Abortion is the most common complication in the first half of pregnancy. Its incidence varies between 20-25%. Miscarriage is 2.6 times as likely 17% of cases are expected to present complications later in pregnancy.
- 4. ETIOLOGY Embryonic abnormalities Maternal factors Anatomic factors Endocrine factors Infectious factors Immunologic factors
- 5. CLINICAL FEATURES The pregnant patient complains of : • Bleeding per vaginum • Pain
- 6. INVESTIGATIONS Blood Urine Pelvic examination Ultrasonography
- 7. Transvaginal Sonography Well formed gestational sac Observation of fetal cardiac activity With these there is about 98% chance of continuation of pregnancy. Sonography can usually differentiate between an intrauterine pregnancy (viable or non-viable), a molar pregnancy, or an inevitable abortion.
- 8. Serum Progesterone value 25 ng/ml or more – a viable pregnancy in about 95% cases Serial serum beta HCG level 20 ng/ml or more – viable pregnancy To assess the level of fetal well being
- 9. Adverse Prognostic factors in cases of Threatened Abortion A large empty gestational sac Discrepancy : gestational age and crown to rump length Fetal bradycardia or absence of fetal heart activity Advanced maternal age History of recurrent pregnancy loss Maternal serum Progesterone < 25 ng/ml or low maternal serum hCG
- 10. Complications These fetuses are at increased risk for intrauterine growth retardation, preterm delivery, low birthweight, and perinatal death. Maternal risks include antepartum hemorrhage, manual removal of the placenta, and cesarean delivery.
- 11. Management Bed rest Paracetamol Progesterone therapy hCG therapy Tocolytic agents
- 12. “There is insufficient evidence of high quality that supports a policy of bed rest in order to prevent miscarriage in women with confirmed fetal viability and vaginal bleeding in first half of pregnancy”.
- 13. Progesterone therapy Oral micronized Progesterone : 200mg OD or BD. Vaginal progesterone suppositories : 200mg OD or BD. Progesterone vaginal gel : 100mg two or three times/day Intramuscular Progesterone : Injection in oil given as 50mg /day.
- 14. • “Use of progestogens is effective in the treatment of threatened miscarriage with no evidence of increased rates of pregnancy- induced hypertension or antepartum haemorrhage as harmful effects to the mother, nor increased occurrence of congenital abnormalities on the newborn”. •“However, the analysis was limited by the small number and the poor methodological quality of eligible studies (four studies) and the small number of the participants (421), which limit the power of the meta-analysis and hence of this conclusion”.
- 15. “The current evidence does not support the routine use of hCG in the treatment of threatened miscarriage”.
- 16. Tocolytics Adrenergic receptor agonists Ca2+ channel blockers Oxytocin-receptor antagonist: Atosiban Nitric oxide donors Magnesium sulphate Cycloxygenase inhibitors
- 17. Sites of action of tocolytic drugs in the uterine myometrium
- 18. Ritodrine Started as 50 µg/min i.v. infusion Rate of infusion is increased every 10 minutes till uterine contractions cease or maternal heart rate rises to 120/min. Contractions can also be kept suppressed by 10 mg i.m. 4-6 hourly followed by 10 mg oral 4-6 hourly.
- 19. Side effects & contraindications Tachycardia, Hypotension, Pulmonary Edema. Hypergylycemia, Hypokalemia. Anxiety, Restlessness, Headaches. Fetal pulmonary edema. Neonate may develop hypoglycemia and ileus. Its use is contraindicated if mother is diabetic, having heart disease, or receiving beta blockers.
- 20. Ca2+ channel blockers Relative to Beta2 adrenergic agonists, Nifedipine is more likely to improve fetal outcomes and less likely to cause maternal side effects. Oral Nifedipine 10 mg repeated once or twice after 20-30 min, followed by 10 mg, 6 hourly has been used.
- 21. Nifedipine: side effects Maternal flushing Headache, Dizziness, Nausea Transient hypotension and Tachycardia, Palpitations. Fetal hypoxia associated with maternal Hypotension.
- 22. Oxytocin receptor antagonists Atosiban : a peptide analogue of Oxytocin Competitively inhibits the interaction of Oxytocin with its membrane receptor on uterine cellsdecreases the frequency of uterine contractions. Intravenous use 6.75 mg bolus, followed by 300µg/min infusion for 3 hours. Then 100µg/hour for upto 45 hours.
- 23. Nitroglycerine Nitric oxide is a potent vasodilator and smooth muscle relaxant. The major adverse effect is maternal hypotension. Dose; 50-200µg intravenously. Can consider repeating dose after 1-4 minutes if inadequate response occurs.
- 24. Magnesium Sulphate Administered intravenously ; 4-6 g loading dose, then 2-4 g/hour titrated to uterine response and maternal toxicity. Two reviews demonstrate magnesium sulphate to be ineffective as a tocolytic.
- 25. Side effects of magnesium sulphate Maternal flushing, Sweating, Respiratory depression, Bradycardia, Myocardial depression, Loss of deep tendon reflexes, Neuromuscular blockade.
- 26. “There is insufficient evidence to support the use of uterine muscle relaxant drugs for women with threatened miscarriage”. “Any such use should be restricted to the context of randomised trials”.
- 27. Cycloxygenase inhibitor Indomethacin Use is controversial.
- 28. Anti-D Immunoglobulin The Rh-negative woman is given anti-D immunoglobulin following abortion. This practice is controversial with threatened abortion because it lacks evidence-based support (American College of Obstetricians and Gynecologists, 1999; Weissman and associates, 2002).
Notes de l'éditeur
- Miscarriage is a common complication encountered during pregnancy. The role of progesterone in preparing the uterus for the implantation of the embryo and its role in maintaining the pregnancy have been known for a long time. Inadequate secretion of progesterone in early pregnancy has been linked to the aetiology of miscarriage and progesterone supplementation has been used as a treatment for threatened miscarriage to prevent spontaneous pregnancy loss
- Threatened abortion is manifested by vaginal bleeding, with or without abdominal pain, while the cervix is closed and the fetus is viable and inside the uterine cavity ( Cunningham 2001a). Threatened Abortion is the most common complication in the first half of pregnancy. Its incidence varies between 20-25%.
- 1.Embryonic abnormalities account for 80-90% of first-trimester miscarriages 2.Chronic maternal health factors: Maternal insulin-dependent diabetes mellitus, Severe hypertension, Renal disease, Systemic lupus erythematosus, Hypothyroidism-There are three possible explanations for the assumed association of thyroid autoimmunity with miscarriage: 1) pregnancy loss is an epiphenomenon and not a direct effect of the thyroid autoantibodies, the presence of thyroid autoantibodies reflecting a generalized activation of the immune system; 2) delayed conception from the presence of thyroid autoantibodies; hence, when women with thyroid autoimmunity become pregnant, face a higher risk of miscarriage because of older age; and 3) the pregnancy loss is secondary to a subtle deficiency in thyroid hormone concentrations or a lower capacity of the thyroid to adequately adapt to the demands of pregnancy., and hyperthyroidism Acute maternal health factors: Infections (eg, rubella, cytomegalovirus [CMV], and mycoplasma, ureaplasma, listeria, toxoplasma infections) Trauma Severe emotional shock Exogenous factors:Alcohol, Tobacco, Cocaine and other illicit drugs 3. Anatomic factors: Congenital or acquired anatomic factors are reported to occur in 10-15% of women who have recurrent spontaneous abortions. Congenital anatomic lesions include müllerian duct anomalies (eg, septate uterus, diethylstilbestrol [DES]-related anomalies). Müllerian duct lesions usually are found in second-trimester pregnancy loss. Anomalies of the uterine artery with compromised endometrial blood flow are congenital. Acquired lesions include intrauterine adhesions (ie, synechiae), leiomyoma, and endometriosis. Congenital or acquired uterine defects, fibroids, cervical incompetence, abnormal placental development, or grand multiparity. 4. Endocrine factors: Endocrine factors potentially contribute to recurrent abortion in 10-20% of cases. Luteal phase insufficiency (ie, abnormal corpus luteum function with insufficient progesterone production) is implicated as the most common endocrine abnormality contributing to spontaneous miscarriage. Hypothyroidism, hypoprolactinemia, poor diabetic control, and polycystic ovarian syndrome are contributive factors in pregnancy loss. 5. Infectious factors: Presumed infectious etiology may be found in 5% of cases. Bacterial, viral, parasitic, fungal, and zoonotic infections are associated with recurrent spontaneous miscarriage. 6. Immunologic factors: Immunologic factors may contribute in up to 60% of recurrent spontaneous miscarriages. Both the developing embryo and the trophoblast may be considered immunologically foreign to the maternal immune system. Antiphospholipid antibody syndrome generally is responsible for more second-trimester pregnancy losses than first-trimester losses. 7. Miscellaneous factors Miscellaneous factors may account for up to 3% of recurrent spontaneous miscarriages. Other contributing factors implicated in sporadic and recurrent spontaneous abortions include environment, drugs, placental abnormalities, medical illnesses, and male-related causes. Gestational exposure to nonaspirin NSAIDs may increase the risk for miscarriage. Exposure to NSAIDs was not found to be an independent risk factor for miscarriage, with the exception of indomethacin, which, the study indicated, is significantly associated with spontaneous abortion following first-trimester exposure.
- With miscarriage, bleeding usually begins first, and cramping abdominal pain follows a few hours to several days later. The pain may present as anterior and clearly rhythmic cramps; as a persistent low backache, associated with a feeling of pelvic pressure; or as a dull, midline, suprapubic discomfort. Whichever form the pain takes, the combination of bleeding and pain predicts a poor prognosis for pregnancy continuation. The main reasons for vaginal bleeding in early pregnancy are subchorionic haemorrhage, subchorionic haematoma and rupture of a marginal placental sinus.2 In majority of the cases of threatened abortion the bleeding is of unknown origin and usually slight
- Abdominal or vaginal ultrasound may be done to check the baby's development, heart beat, and amount of bleeding. A pelvic exam will be done to check the cervix. The following blood tests may be performed: Beta HCG (quantitative) test over a period of days or weeks to confirm whether the pregnancy is continuing Complete blood count (CBC) to determine amount of blood loss Pregnancy test to confirm pregnancy Progesterone level White blood count (WBC) with differential to rule out infection
- The main reasons for vaginal bleeding in early pregnancy are subchorionic haemorrhage, subchorionic haematoma and rupture of a marginal placental sinus.
- Refrences
- Human placenta, decidua, and fetal membranes are the major sites of production and secretion of inhibin A and activin A in maternal serum, amniotic fluid, and umbilical cord blood. Inhibins (inhibin A, B, total inhibin) play a very important role in the regulation of female reproduction. Inhibin A is produced in the ovaries, adrenals, spleen, bone marrow, placenta and fetal membranes. This peptide plays main role in obstetrics. Inhibin B is secreted mainly in ovaries and its function is focused on gynecology. In practice, evaluation of serum total inhibin levels can be important in the diagnosis of polycystic ovary syndrome and ovarian tumors. According to current knowledge inhibin A can be used in the diagnosis of ectopic pregnancy, hydatidiform mole, threatening abortion, pre-eclampsia and pregnancy associated with Down's syndrome. There are requirements of further studies to clarify the use of inhibins in clinical practice of reproductive endocrinology.
- Complications occur in 17% cases.
- There are no effective therapies for threatened abortion. Transvaginal sonography, Serial serum quantitative human chorionic gonadotropin (hCG), and Serum progesterone levels, are analyzed to ascertain if the fetus is alive. To date, the mechanism of action of paracetamol is not completely understood. The main mechanism proposed is the inhibition ofcyclooxygenase (COX), and recent findings suggest that it is highly selective for COX-2.[85] Because of its selectivity for COX-2 it does not significantly inhibit the production of the pro-clotting thromboxanes. Avoid or restrict some forms of activity. Not having sexual intercourse is usually recommended until the warning signs have disappeared. The use of progesterone is controversial. It might relax smooth muscles, including the muscles of the uterus. However, it also might increase the risk of an incomplete abortion or an abnormal pregnancy. Unless there is a luteal phase defect, progesterone should not be used.
- Progesterone is secreted by the ovary, mainly from the corpus luteum, during the second half of the menstrual cycle (Figure 40–3). LH, acting via its G protein-coupled receptor, stimulates progesterone secretion during the normal cycle. After fertilization, the trophoblast secretes hCG into the maternal circulation, which then stimulates the LH receptor to sustain the corpus luteum and maintain progesterone production. During the second or third month of pregnancy, the developing placenta begins to secrete estrogen and progesterone in collaboration with the fetal adrenal glands, and thereafter the corpus luteum is not essential to continued gestation. Estrogen and progesterone continue to be secreted in large amounts by the placenta up to the time of delivery Progesterone decreases estrogen-driven endometrial proliferation and leads to the development of a secretory endometrium (Figure 40–3), and the abrupt decline in progesterone at the end of the cycle is the main determinant of the onset of menstruation. If the duration of the luteal phase is artificially lengthened, either by sustaining luteal function or by treatment with progesterone, decidual changes in the endometrial stroma similar to those seen in early pregnancy can be induced. Under normal circumstances, estrogen antecedes and accompanies progesterone in its action on the endometrium and is essential to the development of the normal menstrual pattern. Progesterone also influences the endocervical glands, and the abundant watery secretion of the estrogen-stimulated structures is changed to a scant viscid material. As noted previously, these and other effects of progestins decrease penetration of the cervix by sperm. The estrogen-induced maturation of the human vaginal epithelium is modified toward the condition of pregnancy by the action of progesterone, a change that can be detected in cytological alterations in the vaginal smear. If the quantity of estrogen concurrently acting is known to be adequate, or if it is assured by giving estrogen, the cytological response to a progestin can be used to evaluate its progestational potency. Progesterone is very important for the maintenance of pregnancy. Progesterone suppresses menstruation and uterine contractility, but other effects also may be important. These effects to maintain pregnancy led to the historical use of progestins to prevent threatened abortion. However, such treatment is of questionable benefit, probably because spontaneous abortion infrequently results from diminished progesterone. Progesterone undergoes rapid first-pass metabolism, but high-dose (e.g., 100-200 mg) preparations of micronized progesterone (PROMETRIUM) are available for oral use. Although the absolute bioavailability of these preparations is low (Fotherby, 1996), efficacious plasma levels nevertheless may be obtained. Progesterone also is available in oil solution for injection, as a vaginal gel (CRINONE, PROCHIEVE), as a slow-release intrauterine device (PROGESTASERT) for contraception, and as a vaginal insert (ENDOMETRIN) for assisted reproductive technology. Esters such as MPA (DEPO-PROVERA) are available for intramuscular administration, and MPA (PROVERA, others) and megestrol acetate (MEGACE, others) may be used orally. The 19-nor steroids have good oral activity because the ethinyl substituent at C17 significantly slows hepatic metabolism. Implants and depot preparations of synthetic progestins are available in many countries for release over very long periods of time (see later section on contraceptives). In the plasma, progesterone is bound by albumin and corticosteroid-binding globulin but is not appreciably bound to SHBG. 19-Nor compounds, such as norethindrone, norgestrel, and desogestrel, bind to SHBG and albumin, and esters such as MPA bind primarily to albumin. Total binding of all these synthetic compounds to plasma proteins is extensive, 90%, but the proteins involved are compound specific. The elimination t1/2 of progesterone is 5 minutes, and the hormone is metabolized primarily in the liver to hydroxylated metabolites and their sulfate and glucuronide conjugates, which are eliminated in the urine. A major metabolite specific for progesterone is pregnane-3, 20 -diol; its measurement in urine and plasma is used as an index of endogenous progesterone secretion. The synthetic progestins have much longer half-lives (e.g., 7 hours for norethindrone, 16 hours for norgestrel, 12 hours for gestodene, and 24 hours for MPA). The metabolism of synthetic progestins is thought to be primarily hepatic, and elimination is generally via the urine as conjugates and various polar metabolites, although their metabolism is not as clearly defined as that of progesterone. Discontinue progesterone between 9 and 12 weeks of gestation. 250 mg/week of intramuscular 17-hydroxyprogesterone caproate (Meis et al., 2003). Vaginal administration of progesterone (200 mg each night) also was used in one clinical trial with apparent efficacy (Fonseca et al., 2007) Progestogens are a group of hormones, which bind to the progesterone receptors; they include both the natural female sex hormone progesterone and the synthetic forms. Progesterone is secreted during early pregnancy from the ovary by corpus luteum (Cunningham 2001b). It is an essential hormone for the establishment and maintenance of pregnancy by inducing secretary changes in the lining of the uterus, which are important for implantation of the fertilised ovum (Jin 2006). Progesterone modulates the immune response of the mother to prevent rejection of the embryo and it enhances uterine quiescence and suppresses uterine contractions (Szekeres-Bartho 2008; Szekeres-Bartho 2009). Low progesterone levels have been linked to increased risk of first trimester miscarriage (Osmana ao lu 2010).
- The Th2-derived cytokines, IL-4 and IL-6, induce the release of hCG from trophoblasts and the hCG stimulates progesterone production from corpus luteum in pregnancy. Progesterone has been shown to stimulate the secretion of Th2 and reduces the secretion of Th1 cytokines. Thus, maintenance of pregnancy has been attributed to Th2 type cytokine. This role in controlling the immune and endocrine system which promotes the function of the trophoblasts at the implantation site seems interesting.4 Use of progestogen in threatened abortion is controversial.5 Progesterone is largely produced by the corpus luteum until about 10 weeks of gestation.1 A study in ovarian failure and Assisted reproduction it was shown that one hundred mg of P were probably a supraphysiological dose to support pregnancy 6 to 8 weeks after conception. The fetoplacental unit was competent from 10 to 12 weeks’ gestation.2 When the pregnancy reaches term gestation, progesterone levels range from 100-200 ng/ml and the placenta produces about 250 mg/day. Almost all of the progesterone produced by the placenta enters the placenta, contrast to oestrogen. Progesterone production is independent of he precursor available, fetal status including the wellbeing. In early pregnancy, the maternal levels of 17 a-hydroxyprogesterone rise, marking the activity of the corpus luteum. By the tenth week of gestation, this compound has returned to baseline levels, indicating that the placenta has little 17a hydroxylase activity. However, beginning about the 32nd week there is a second, more gradual rise in 17a-hydroxyprogesterone due to placental utilization of fetal precursors. This is relevant to understand prevention of preterm labor. Progesterone is also important in suppressing the maternal immunologic response to fetal antigens, thereby preventing maternal rejection of the trophoblast. And, of course, progesterone prepares and maintains the endometrium to allow implantation earlier. Studies have shown that the human corpus luteum makes significant amounts of estradiol, but it is progesterone and not oestrogen that is required for successful implantation.3
- Miscarriage is a common occurrence in early pregnancy. Human chorionic gonadotrophin (hCG) is secreted by the syncytiotrophoblast. It promotes the corpus luteum to secrete progesterone and helps in maintaining the pregnancy. Hence, there has been much interest in the use of hCG to treat threatened miscarriage.
- Adrenergic receptor agonists relax the myometrium by activating the cyclic AMP-PKA signaling cascade that phosphorylates and inactivates myosin light-chain kinase, a key enzyme in uterine contraction. Beta-adrenergic receptors are coupled to a stimulatory G protein of adenylyl cyclase. This enzyme produces the second messenger cyclic adenosine monophosphate (cAMP). In the lung, cAMP decreases calcium concentrations within cells and activates protein kinase A. Both of these changes inactivate myosin light chain kinase and activate myosin light chain phosphatase. In addition, beta-2 agonists open large conductance calcium-activated potassium channels and thereby tend to hyperpolarize airway smooth muscle cells. The combination of decreased intracellular calcium, increased membrane potassium conductance, and decreased myosin light chain kinase activity leads to smooth muscle relaxation and bronchodilation.
- tachycardia secondary to peripheral vasodilation and cardiac stimulation; tachycardia can be accompanied by palpitations. tremor, sweats, agitation. more severe effects, pulmonary edema, myocardial ischemia, cardiac arrhythmia, are exceptional. Hyperglycemia , steroids Most side effects of beta-2 agonists result from their concurrent beta-1 activity, and include increase in heart rate, rise in systolic pressure, decrease in diastolic pressure, chest pain secondary to MI, and arrhythmia. Beta agonists may also cause fluid retention secondary to decrease in water clearance, which when added to the tachycardia and increased myocardial work, may result incardiac failure. In addition, they increase gluconeogenesis in the liver and muscle resulting in hyperglycemia, which increases insulin requirements in diabetic patients. The passage of beta-agonists through the placenta does occur and may be responsible for fetal tachycardia, as well as hypoglycemia or hyperglycemia at birth. It is contraindicated in patients with type 2 diabetes, high blood pressure or migraine. It has also been associated with post-partum hemorrhage.
- Ca2+ channel blockers inhibit the influx of Ca2+ through depolarization-activated, voltage-sensitive Ca2+ channels in the plasma membrane, thereby preventing the activation of myosin light-chain kinase and the stimulation of uterine contraction.
- Atosiban is a nonapeptide, desamino-oxytocin analogue, and a competitive vasopressin/oxytocin receptor antagonist (VOTra). Atosiban inhibits the oxytocin-mediated release of inositol trisphosphate from the myometrial cell membrane. As a result, there is reduced release of intracellular, stored calcium from the sarcoplasmic reticulum of myometrial cells, and reduced influx of Ca2+ from the extracellular space through voltage gated channels. In addition, atosiban suppresses oxytocin-mediated release of PGE and PGF from the decidua. In a recent meta-analysis, nifedipine is superior to β2-adrenergic-receptor agonists and magnesium sulfate for tocolysis in women with preterm labor (20–36 weeks), but it has been assigned to pregnancy category C by the Food and Drug Administration (FDA) so is not recommended before 20 weeks, or in the first trimester. Recent reports supports the use of atosiban, even at very early pregnancy, to decrease the frequency of uterine contractions to enhance success of pregnancy. Book ; Clinical Pharmacology During Pregnancy edited by Donald Mattison
- Nitric oxide detail
- Progesterone is secreted by the ovary, mainly from the corpus luteum, during the second half of the menstrual cycle (Figure 40–3). LH, acting via its G protein-coupled receptor, stimulates progesterone secretion during the normal cycle. After fertilization, the trophoblast secretes hCG into the maternal circulation, which then stimulates the LH receptor to sustain the corpus luteum and maintain progesterone production. During the second or third month of pregnancy, the developing placenta begins to secrete estrogen and progesterone in collaboration with the fetal adrenal glands, and thereafter the corpus luteum is not essential to continued gestation. Estrogen and progesterone continue to be secreted in large amounts by the placenta up to the time of delivery Progesterone decreases estrogen-driven endometrial proliferation and leads to the development of a secretory endometrium (Figure 40–3), and the abrupt decline in progesterone at the end of the cycle is the main determinant of the onset of menstruation. If the duration of the luteal phase is artificially lengthened, either by sustaining luteal function or by treatment with progesterone, decidual changes in the endometrial stroma similar to those seen in early pregnancy can be induced. Under normal circumstances, estrogen antecedes and accompanies progesterone in its action on the endometrium and is essential to the development of the normal menstrual pattern. Progesterone also influences the endocervical glands, and the abundant watery secretion of the estrogen-stimulated structures is changed to a scant viscid material. As noted previously, these and other effects of progestins decrease penetration of the cervix by sperm. The estrogen-induced maturation of the human vaginal epithelium is modified toward the condition of pregnancy by the action of progesterone, a change that can be detected in cytological alterations in the vaginal smear. If the quantity of estrogen concurrently acting is known to be adequate, or if it is assured by giving estrogen, the cytological response to a progestin can be used to evaluate its progestational potency. Progesterone is very important for the maintenance of pregnancy. Progesterone suppresses menstruation and uterine contractility, but other effects also may be important. These effects to maintain pregnancy led to the historical use of progestins to prevent threatened abortion. However, such treatment is of questionable benefit, probably because spontaneous abortion infrequently results from diminished progesterone. Progesterone undergoes rapid first-pass metabolism, but high-dose (e.g., 100-200 mg) preparations of micronized progesterone (PROMETRIUM) are available for oral use. Although the absolute bioavailability of these preparations is low (Fotherby, 1996), efficacious plasma levels nevertheless may be obtained. Progesterone also is available in oil solution for injection, as a vaginal gel (CRINONE, PROCHIEVE), as a slow-release intrauterine device (PROGESTASERT) for contraception, and as a vaginal insert (ENDOMETRIN) for assisted reproductive technology. Esters such as MPA (DEPO-PROVERA) are available for intramuscular administration, and MPA (PROVERA, others) and megestrol acetate (MEGACE, others) may be used orally. The 19-nor steroids have good oral activity because the ethinyl substituent at C17 significantly slows hepatic metabolism. Implants and depot preparations of synthetic progestins are available in many countries for release over very long periods of time (see later section on contraceptives). In the plasma, progesterone is bound by albumin and corticosteroid-binding globulin but is not appreciably bound to SHBG. 19-Nor compounds, such as norethindrone, norgestrel, and desogestrel, bind to SHBG and albumin, and esters such as MPA bind primarily to albumin. Total binding of all these synthetic compounds to plasma proteins is extensive, 90%, but the proteins involved are compound specific. The elimination t1/2 of progesterone is 5 minutes, and the hormone is metabolized primarily in the liver to hydroxylated metabolites and their sulfate and glucuronide conjugates, which are eliminated in the urine. A major metabolite specific for progesterone is pregnane-3, 20 -diol; its measurement in urine and plasma is used as an index of endogenous progesterone secretion. The synthetic progestins have much longer half-lives (e.g., 7 hours for norethindrone, 16 hours for norgestrel, 12 hours for gestodene, and 24 hours for MPA). The metabolism of synthetic progestins is thought to be primarily hepatic, and elimination is generally via the urine as conjugates and various polar metabolites, although their metabolism is not as clearly defined as that of progesterone.