Single progestin for help in pregnancy, menopause
Experts discuss various benefits from use of dydrogesterone
Progesterone prepares the endometrium for implantation and facilitates endometrial development. "It is important to have sufficient levels of progesterone to form progesterone-induced blocking factor (PIBF), said Dr. Walfrido Sumpaico, chair of the department of obstetrics and gynecology at the East Avenue Medical Center. PIBF maintains a good level of the Th2 cytokine for a successful pregnancy, he explained in a symposium organized by Solvay Pharma Inc. Philippines. He also identified the administration of exogenous progesterone, dydrogesterone (Duphaston), as the most logical approach to induce PIBF production.
In the same symposium, Dr. Ditas Decena, associate professor at the University of Santo Tomas, discussed the efficacy and safety of dydrogesterone in the management of dysfunctional uterine bleeding (DUB). Dr. Susan Nagtalon, assistant professor at the University of the East-Ramon Magsaysay Memorial Medical Center, discussed the role of dydrogesterone in postmenopausal hormone-replacement therapy (HRT), specifically in relief of vasomotor symptoms, vulgovaginal atrophy, and prevention of bone loss in early post menopause. Dr. Eileen Manalo, associate professor at the University of the Philippines College of Medicine, discussed the differences among the progestins.
How progesterone works
"Successful mammalian pregnancy depends upon tolerance of a genetically incompatible fetus by the maternal immune system. The immunotolerance on the part of the mother depends on the interaction of cytokines," said Sumpaico.
Cytokines mediate and regulate immunity. Responses to cytokines include increasing or decreasing expression of membrane proteins (including cytokine receptors), proliferation, and secretion of effector molecules
Sumpaico said that the initial cytokine action is Th1 cytokine because this is important for the blastula to invade the endometrium and have trophoblastic invasion and induction of angiogenesis. But thereafter, these cytokines are detrimental and their response must be counteracted by the antiinflammatory cytokines. If Th1 cytokines persist, miscarriage results.
Critical for the balance between Th1 and Th2 cytokine production are CD8+ T cells, progesterone, and a low-molecular-weight factor. In the presence of progesterone, the lymphocytes will produce a 34-kilodalton mediator protein called PIBF-the substance important for the antiabortive effects because it induces the production of Th2 cytokines and downregulates the expression of the prothrombinase FG12.
The lack of PIBF results in increased natural-killer-cell (NK) activity. In the presence of PIBF there would be very little interferon gamma, low natural-killer-cell activity, and therefore a normal pregnancy. On the other hand, the presence of progesterone-receptor-blocker RU-486 or mifepristone will negate the presence of PIBF; therefore, IFN gamma proliferates, then high natural-killer-cell activity and abortion would result.
Sumpaico stressed, "What is important is to have sufficient levels of progesterone to form sufficient levels of PIBF and have a shift of bias for the predominance of Th2 to kill off the bad cytokines-natural killer cells, interferon gamma, interkeukin-2-and you protect the fetus."
So the most logical approach is by intervening at the progesterone-receptor level by the administration of exogenous progesterone, he added. Sumpaico cited studies on Duphaston as proof that increasing PIBF protects the fetus and leads to successful pregnancy.
A review of several studies on dydrogesterone since the 1960s showed that positive outcomes were achieved in 275 of 339 patients. A more recent study presented by Prof. Clemens Tempfer at the International Society of Gynecological Endocrinology conference in Florence, Italy, in 2004 showed 80-percent positive outcomes in 67 women who were treated with Duphaston from day 14 of the menstrual cycle until the onset of menstrual flow or up to 20 weeks of gestation.
The most recent study (J Kalinka and JS Bartho, 2005) showed an increase of PIBF level from 453 to 1291 after administration of Duphaston. No differences were seen in terms of missed abortions, preterm delivery, gestational age at delivery, and weight at birth between the control group of healthy women and the group treated with Duphaston.
Know your progestins
Progestins are compounds that transform the endometrium from a proliferative state to a secretory state in an estrogen-primed uterus. Synthetic progestins are steroids with progesterone-like actions derived from different parent compounds. Progestins differ widely in their chemical structure, pharmacokinetics, and potency.
Manalo stressed that it is important for physicians to understand these differences in order to prescribe the optimum type and dose of progestin for HRT.
Natural progesterone has a chemical structure identical to the substance made in a woman's body by the ovarian corpus luteum (gland formed after an egg is ovulated each month). This is to be distinguished from synthetic progesterone-like chemicals called progestogens, which bind to the body's progesterone receptors and function, for the most part, just like progesterone. Because they are chemically different from natural progesterone, they sometimes have side effects.
Dydrogesterone is a retroprogesterone, a stereoisomer of progesterone, with an additional double bond between carbons 6 and 7. The progesterone molecule is almost "flat," the retroprogesterone molecule is bent by a change of the methyl group at carbon 10 from the b position to the a position and the hydrogen at C9 from the a to the b position. In addition, there is an additional double bond between C6 and C7. Dydrogesterone binds almost exclusively to the progesterone receptor. Though the binding affinity appears to be somewhat lower than that of progesterone, due to its better bioavailability and the progestogenic nature of the metabolites, the equivalence dose is 10 to 20 times lower.
Different biologic effects may be produced by administered progestins due to the specific influence of each progestin and its metabolites on the conformation of the progestin receptor and its subsequent activation of transcription in target cells, said Manalo.
Progestogens in medical therapy
Progestogens may be used for HRT and in the treatment of DUB.
DUB is "excessively heavy, prolonged, or frequent bleeding of uterine origin which is not due to pregnancy or to recognizable pelvic or systemic disease." In anovulatory DUB with acyclic (irregular) estrogen production, there will be no progesterone withdrawal from estrogen-primed endometrium and so cycles are irregular. Prolonged estrogen stimulation may cause a buildup of endometrium with erratic bleeding as it breaks down and is expelled. This is the rationale for using cyclical progestogens during the second half of the menstrual cycle to provoke a regular withdrawal bleed. Continuous progestogen is intended to induce endometrial atrophy and hence to prevent estrogen-stimulated endometrial proliferation. Progestogens and estrogens and progestogens in combination are already widely used in the management of irregular or excessive bleeding due to DUB, but the regimen dose, and type of progestogen used varies widely with little consensus about the optimum treatment approach.
Nine out of 10 cases of DUB result from anovulation. Corpus luteum is not developed when the pituitary gland is not able to secrete an adequate amount of gonadotropins or hormones that promote the production of sex hormones and either sperm or ova. When there is no progesterone production, overgrowth of endometrium results. A possible long-term effect is endometrial cancer.
Progesterone mainly has an antiestrogenic effect by decreasing the DNA synthesis and proliferation, Decena explained. It decreases the estrogen receptors and increases the conversion of estradiol to less-potent estrone. When these three factors occur, the endometrium matures and fragility of the endometrium diminishes, thus bleeding ceases.
To stop bleeding, Duphaston is given at 20 mg for 10 days. And for cycle regulation, Decena recommends Duphaston 10 g daily D16-D25 for three to six months.
In HRT, female hormones are used for the relief of symptoms resulting from cessation of ovarian function, either at the time of the natural menopause or following surgical removal of the ovaries. HRT is effective against vasomotor symptoms, genitourinary atrophy, and in preventing osteoporosis. Although risks have also been identified, like coronary heart disease, breast cancer, stroke, and thromboembolism.
Nagtalon cited the study of Genazzani and Otsuki (2004) to show the effects of progestogens on the cardiovascular system. Like estrogen, progesterone has vasodilatory and antiproliferative effects on the vascular smooth-muscle cells. PAR-1 or the postlytic antithrombin receptor antigen expression upregulation, which is responsible for procoagulation activity is found with the natural preparation and not with the synthetic preparation. She added: "As far as homeostasis and coagulation are concerned, there seems to be no demonstrable effect with the use of progestin."
Chang et al. (2005) looked into how conjugated equine estrogen, in combination with medroxyprogesterone or dydrogesterone, affects the risk factors for coronary heart disease in postmenopausal women. For one year, this randomized controlled trial followed up Taiwanese women and found that neither group demonstrated significant changes in protein and prothrombin time. There were also similar reductions in total cholesterol, low-density lipoproteins, antithrombin-3 antigen, and triglycerides. Although both groups showed increases in high-density lipoproteins, the Duphaston group showed higher levels (10.6 percent) than the MPA group (2.7 percent).
Still, it is "difficult to draw conclusions on the possible superiority of a single molecule versus the other," said Nagtalon. "Whether or not dydrogesterone will prove to be a better progestin with regard to the reduction in risk of breast cancer, cardiovascular disease, and dementia still needs to be proven by further randomized controlled trials."
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