Exogenous Progestins Research Articles

Chronic hormone replacement therapy alters thermoregulatory and vasomotor function in postmenopausal women.

This investigation examined effects of chronic (>/=2 yr) hormone replacement therapy (HRT), both estrogen replacement therapy (ERT) and estrogen plus progesterone therapy (E+P), on core temperature and skin blood flow responses of postmenopausal women. Twenty-five postmenopausal women [9 not on HRT (NO), 8 on ERT, 8 on E+P] exercised on a cycle ergometer for 1 h at an ambient temperature of 36 degrees C. Cutaneous vascular conductance (CVC) was monitored by laser-Doppler flowmetry, and forearm vascular conductance (FVC) was measured by using venous occlusion plethysmography. Iontophoresis of bretylium tosylate was performed before exercise to block local vasoconstrictor (VC) activity at one skin site on the forearm. Rectal temperature (Tre) was approximately 0.5 degrees C lower for the ERT group (P < 0.01) compared with E+P and NO groups at rest and throughout exercise. FVC: mean body temperature (Tb) and CVC: Tb curves were shifted approximately 0.5 degrees C leftward for the ERT group (P < 0.0001). Baseline CVC was significantly higher in the ERT group (P < 0.05), but there was no interaction between bretylium treatment and groups once exercise was initiated. These results suggest that 1) chronic ERT likely acts centrally to decrease Tre, 2) ERT lowers the Tre at which heat-loss effector mechanisms are initiated, primarily by actions on active cutaneous vasodilation, and 3) addition of exogenous progestins in HRT effectively blocks these effects.

Use of short-term progestin treatment to resynchronize the second estrus following synchronized breeding in beef heifers

Two trials were conducted to evaluate the efficacy of short-term progestin administration to resynchronize the second estrus after artificial insemination in yearling beef heifers. In Trial 1 crossbred yearling heifers (n = 208) were synchronized with Syncro-Mate-B (SMB) and artificially inseminated (AI) between 48 and 54 h following implant removal. Implant removal is defined as Day 1. Following AI, the heifers were randomly assigned to 1 of 2 experimental groups. Group 1 heifers were fed melengestrol acetate (MGA) daily from Day 17 to 21 at a rate of 0.5 mg/head, while Group 2 control received no exogenous progestin during this period. Synchrony of estrus was defined as the 3-d period in which the highest number of heifers expressed behavioral estrus in each group. There was no difference (P < 0.05) in the pregnancy rate during the second estrus due to MGA supplementation. More MGA-treated heifers (P < 0.01) expressed estrus in a 3-d period than the controls. In Trial 2, yearling heifers (n = 108) were synchronized with 2 injections of PGF 2α (second PGF 2α injection is designated as Day 1) administered 14 d apart with AI 12 h after the onset of behavioral estrus. The heifers were then randomly assigned to 1 of the following 3 treatment groups after initial AI: 1) MGA fed at 0.5 mg/head daily from Days 17 to 21; 2) norgestomet administered in 6.0-mg implants from Days 17 to 21; 3) untreated control heifers. Blood samples were collected on Day 21 and analyzed for progesterone (P 4). Elevated P 4 (> 1 ng/ml) on Day 21 indicated pregnancy to the first insemination. Synchrony among the 3 groups of heifers was similar (P > 0.10); however, the second estrus was less (P < 0.05) variable in the MGA and norgestomet treated heifers. During the resynchronized second estrus, conception rates were not affected by progestin treatment (MGA 40%, norgestomet 64%, and control 62%; P > 0.10). However, a proportion of heifers treated MGA 10% 4 36 and norgestomet 3% 1 36 expressed behavioral estrus during second estrus even though they were diagnosed as pregnant from first service by elevated P 4 levels on Day 21. We conclude that short-term use of progestin from Days 17 to 21 following AI causes closer synchrony of estrus; however, inseminating pregnant heifers that exhibit behavioral estrus may cause abortion.

Medroxyprogesterone attenuates estrogen-mediated inhibition of neointima formation after balloon injury of the rat carotid artery.

Estrogen blunts the neointimal proliferative response to balloon injury of the carotid artery in intact female rats and gonadectomized rats of both sexes. This study tested whether, in gonadectomized rats of both sexes. (1) progestin (medroxyprogesterone acetate, MPA) alters neointima formation in injured carotid arteries, (2) addition of MPA alters the antiproliferative effects of estrogen, and (3) an interaction between MPA and estrogen can be accounted for by MPA-induced alterations in serum 17 beta-estradiol levels. Male and female Sprague-Dawley rats were subjected to gonadectomy, then were randomly divided into four subgroups and treated with either (1) 17 beta-estradiol, (2) MPA, (3) 17 beta-estradiol + MPA, or (4) vehicle, and balloon injury of the right common carotid artery was carried out. Two weeks later, rats were killed by overdose of pentobarbital, and the carotid arteries were subjected to morphometric analysis for evaluation of myointimal thickening. Estradiol inhibited myointimal proliferation after vascular injury in gonadectomized rats of both sexes (P < .05). MPA alone did not alter neointima formation, but addition of MPA to estradiol completely blocked the antiproliferative effects of estrogen without altering serum 17 beta-estradiol levels. These data indicate that exogenous progestin given alone does not alter the vascular injury response in the rat carotid injury model but that addition of a progestin blocks the antiproliferative effects of estrogen in this model. These effects are seen in gonadectomized rats of both sexes. These findings have direct implications for postmenopausal hormone replacement therapy in humans.

Endometrial vasculature in Norplant users.

Disrupted, prolonged and irregular endometrial bleeding are major unwanted side-effects of progestin-only contraceptives. The aim of this paper is to review current information on steroid control of the microvasculature, microvascular heterogeneity and microvascular fragility, with emphasis on the relevance of these issues to the endometrial microvasculature in women receiving Norplant implant contraception. Subjects were either Indonesian women with between 3 and 12 months exposure to Norplant (n = 191) or Caucasian controls recruited in Melbourne, Australia. Norplant endometrium was always thinner than control endometrium, with a varied histology that usually included a basalis-type appearance, signs of haemorrhage and some dilated and congested subepithelial vessels. Thin-walled vessels were seen which could have been either blood vascular or lymphatics. Steroid control of the vasculature can operate through numerous direct and indirect mechanisms, with up to 30 genes relevant to vascular function having consensus oestrogen response elements in their promoter regions. The vasoactive effects of progesterone are less well documented. However, experimental data for direct effects on the endometrial vasculature are mounting. Progestin-induced endometrial breakthrough bleeding is often focal, suggesting that microvascular heterogeneity may be an important factor in understanding this phenomenon. Increased susceptibility to bleeding may result from increased microvascular fragility, possibly as a consequence of progestins altering the balance of angiogenic promoters and inhibitors in the endometrium, thus leaving the vessels in a permanently weakened state.

Use of norplant in women with or at-risk for noninsulin-dependent diabetes

This review addresses the use of Norplant in women with or at-risk for noninsulin-dependent diabetes mellitus (NIDDM). Background information on NIDDM is given, including pathogenesis, effect on glucose and lipid metabolism, and management. The effect of exogenous estrogen and progestogens on glucose tolerance is briefly discussed. In reviewing the effects of Norplant on glucose metabolism, studies on women with normal glucose tolerance were reviewed, along with the one study of Norplant use in women with a past history of gestational diabetes. Norplant does have a minor effect on glucose metabolism. Studies are contradictory regarding lipid metabolism but most suggest that Norplant does not have a negative effect on the high density lipoprotein/total cholesterol ratio. Factors influencing contraceptive choice are reviewed. Protocols for management of Norplant in women with or at-risk for NIDDM are then presented, followed by a case study and a brief discussion. OCP use by women with specific conditions in estimating the potential effects of Norplant use on these conditions. One of these difficult areas is the use of Norplant in women with noninsulin-dependent diabetes mellitus (NIDDM) or in women who are at-risk for NIDDM, ie, those with impaired glucose tolerance (IGT), those with a history of gestational diabetes mellitus (GDM), and those at-risk due to other factors. This article will address the research done with Norplant so as to come to some conclusions regarding the safety of Norplant use in these groups of women.

Effect of preovulatory insertion of Norplant implants over luteinizing hormone secretion and follicular development

To determine whether the process of ovulation could be interrupted by the insertion of Norplant implants (Leiras Pharmaceuticals, Turku, Finland) in the advanced preovulatory phase. Prospective study. The Department of Biomedical Research at the Family Planning Clinic of PROFAMILIA, Santo Domingo, Dominican Republic. Healthy women of reproductive age, requesting Norplant implants contraception. Thirteen of 15 women volunteers who were admitted completed the study. Norplant implants were inserted when the dominant follicle reached a mean diameter of 16 mm, based on serial vaginal ultrasounds (US) beginning on day 10 of the cycle. Blood samples for determination of E2, P, LH, and levonorgestrel, were taken and vaginal US performed at 0, 4, 24, 48, and 72 hours after insertion. If follicle rupture had not occurred at 72 hours after insertion, blood sampling and US were done three times per week during 2 additional weeks. Follicle rupture occurred in 11 of 13 subjects within 72 hours after insertion, with the exception of 1 subject in whom rupture occurred between 72 and 192 hours. Two women already had an LH peak at the time of insertion. In 9 of the remaining 11 women, a shortlasting, blunted LH surge was observed at 4 hours postinsertion. In the remaining two women, who had the lowest E2 levels, ovulation was inhibited, and a persistent follicle developed without luteinization. The insertion of Norplant implants in the advanced follicular phase will not inhibit ovulation if sufficient E2 priming has occurred. On the contrary, the exogenous progestin may rapidly foster ovulation shortly after.

Application of knowledge about corpus luteum function in control of estrus and ovulation in cattle

Understanding corpus luteum (CL) function has led to development of methods of estrus synchronization in cattle that either extend the estrous cycle by administration of exogenous progestins or shorten the cycle by induction of luteolysis. Both methods have limitations, which have been reduced or overcome through sequential or combined treatment with progestin and luteolytic drugs. Future improvements in estrus synchronization methodology are most likely to come from achieving more synchrony between the development of a highly fertile ovulatory follicle and control of luteal function.

Embryotoxicity of a Regressing Corpus Luteum in Beef Cows Supplemented with Progestogen1

Postpartum cows with short-lived corpora lutea produce embryos that arrive at the uterus, but pregnancy rates are low even with exogenous progestogen. Four experiments were conducted to determine whether prostaglandin (PG) F2 alpha, known to cause early luteolysis, could have a direct effect on embryonic loss. Exogenous progestogen was injected s.c. twice daily in each experiment, starting 3 or 4 days after estrus (day of estrus = Day 0). Nonlactating, cycling beef cows were mated and injected i.m. every 8 h on Days 4 through 7 (experiment 1) or 5 through 8 (experiment 3) with either 15 mg PGF2 alpha or 3 ml saline. In experiment 1, cows in a third group received 1 g flunixin meglumine i.m. every 8 h. Ten of 18 PGF2 alpha-treated cows in experiment 3 were luteectomized on Day 5. Pregnancy rates were higher (p < 0.05) in cows given saline or flunixin meglumine (5 of 7) than in cows given PGF2 alpha (1 of 5) in experiment 1, and in cows given saline (6 of 9) or given PGF2 alpha, and luteectomized (8 of 10) than in cows given PGF2 alpha (2 of 8) in experiment 3. Postpartum beef cows, mated at weaning-induced first estrus, received i.m. injections every 8 h on Days 4 through 9 of 3 ml saline or 1 g flunixin meglumine (experiment 2); 14 flunixin meglumine-treated cows were luteectomized on Day 7. Pregnancy rates were higher in cows given flunixin meglumine and luteectomized (7 of 14) than in cows given saline (4 of 15) or flunixin meglumine alone (3 of 15; p < 0.05). In experiment 4, postpartum cows were luteectomized or sham-operated on Day 5. Pregnancy rates (2 of 13 and 2 of 14, respectively) did not differ. Thus, both reduction of endogenous PGF2 alpha and luteectomy were required for embryo survival in postpartum cows with short-lived corpora lutea, whereas luteectomy alone prevented effects of exogenous PGF2 alpha in cycling cows.

Steroid transformations in pregnant mares: Metabolism of exogenous progestins and unusual metabolic activity in vivo and in vitro

The mare possesses unique steroid hormone metabolic activity during pregnancy in that peripheral 4-pregnene-3,20-dione (progesterone; P4) is undetectable by 220 days gestation. This study examines in vivo metabolism of progestins by the pregnant mare and in vitro metabolic activity of maternal and fetal tissues. Pregnant mares (n = 3) received intravenous infusions of 3β-hydroxy-5-pregnen-20-one (pregnenolone; P5), P4, 5α-pregnane-3,20-dione (5α-DHP), 3β-hydroxy-5α-pregnan-20-one (3β-5α), deuterium labeled (D4)-P5, D4-3β-5α and vehicle. Anestrous mares (n = 2) were infused with P5, P4, and vehicle. Also, placenta, endometrium, fetal gonad, maternal and fetal liver, and adrenal from 4 animals were incubated in D4-P5, D4-5α-DHP, or D4-3β-5α. Pregnant mares (in vivo) converted infused P5 predominantly to 5-pregnene-3β,20β-diol (P5-ββ), 5α-DHP, 20α-hydroxy-5α-pregnan-3-one (20α-5α), and 3β-5α while only minor concentrations of P4 were detected. Infused P4 was converted primarily to 5α-DHP and 20α-hydroxypregnanes and when 5α-DHP served as a substrate, other 5α-pregnanes were formed. Infused 3β-5α was either reduced to βα-diol or oxidized to 5α-DHP. Regardless of treatment, anestrous mares were incapable of producing any 20α-hydroxypregnanes but could convert P5 to P5-ββ and P4 in quantities similar to that of pregnant mares. In vitro, placenta converted D4-P5 to D4-P4 while D4-3β-5α was oxidized to D4-5α-DHP. Endometrium converted substrate primarily to D4-20α-hydroxypregnanes. Both maternal and fetal liver produced D4-20β-hydroxy compounds regardless of substrate. Maternal and fetal adrenal were capable of conversion of D4-P5 to D4-P4 while fetal gonad did not perform any significant metabolism of substrate, though it produced P5. These data explain the absence of P4 and presence of other progestin metabolites in maternal circulation during mid- and late pregnancy. Pregnenolone can be 5α-reduced to 3β-5α, and 3β-5α could be 3-oxidized to 5α-DHP. It is 5α-DHP that may serve as substrate for other 5α-pregnanes.

Links between hormone replacement therapy and neoplasia

To evaluate the literature on exogenous estrogens and progestins on risk of breast and endometrial cancers.Review of epidemiologic literature.Population- and hospital-based studies.Postmenopausal women.Sex steroid hormone in hormone replacement regimens.Breast carcinoma and endometrial carcinoma.Estrogens cause cell proliferation in in vitro systems and enhance tumor formation in carcinogen-exposed animal models. Estrogen effects in humans vary by tissue type, exposure patterns, and subject groups. Doses commonly used for estrogen replacement therapy (ERT) are sufficient to cause proliferation, hyperplasia, and carcinoma of the endometrium. After 10 to 15 years of estrogen use, endometrial cancer risk increases nearly 10-fold, but the cancers produced are generally of low grade and stage with an excellent prognosis. Adding a progestin for > or = 10 d/mo reduces or eliminates the estrogen-induced risk. Breast tissue responds differently to sex steroid hormones. Long-term estrogen use increases breast cancer risk modestly (relative risk approximately 1.3 to 1.5). Particular subgroups, such as those with family history, benign proliferative disease, or late natural menopause, may experience greater risk. None of these characteristics are sufficiently well defined to be clear-cut contraindications to ERT. Adding a progestin does not improve the situation; relative risks may be higher for estrogen plus progestin than for estrogen alone. The effect of low dose progestin, e.g., 2.5 mg Provera, administered continuously with the estrogen, is not known. A small increase in relative risk has a large impact on number of women developing breast cancer because of the high baseline rates. For U.S. women age 65, the baseline rate is 210 new cases per 100,000 women per year. A relative risk as small as 1.2 increases a women's chances of developing breast cancer each year from 1 in 250 to 1 in 200.

Metabolic effects of estrogens and progestins

To review the effects of exogenous estrogen and progestin on metabolic risk factors for coronary artery disease in women.Review of selected literature.Population studies and clinical trials.Premenopausal and postmenopausal women.Exogenous gonadal hormones in oral contraceptives and hormone replacement regimens.Lipoprotein, hemostatic, carbohydrate, and blood pressure metabolic parameters.Favorable lipoprotein changes have been demonstrated in both observational studies and clinical trials of effects of exogenous hormones on cardiovascular risk factors in women. These include declines in low-density lipoprotein, apoprotein B, and lipoprotein(a), and increases in high-density lipoprotein (HDL), HDL2, and apoprotein A-I. Hormone replacement effects on triglyceride are minor and, in most patients, probably benign. Evidence is unconvincing that clinically significant changes in clotting factors, carbohydrate metabolism, or blood pressure take place as a result of postmenopausal hormone interventions. In fact, carbohydrate metabolism and blood pressure may be improved slightly. Metabolic studies do not, thus far, provide any contraindications to either estrogen replacement therapy (ERT) or hormone replacement therapy (HRT) in appropriately selected subjects. However, because studies of metabolic risk factors generally have been done in patients who were not hyperlipidemic, hypercoagulable, hyperglycemic, or hypertensive, little is known about the metabolic effects of ERT or HRT on pre-existing metabolic abnormalities.

Effects of progestogens on human endometrium.

The effect of progestogens on endometrium depends on the dosage, duration of exposure, the type of progestogen, and the presence or absence of estrogen. Mechanisms of progestogen action in endometrium are mainly expressed through the binding of hormone to specific nuclear receptors. Exogenous progestogens seem to influence the hypothalamic-pituitary-ovarian-endometrial axis differently in different individuals. Endogenous hormones resulting from ovarian secretion have effects on the endometrium independent of, and in combination with, exogenous progestogens. Endometrial morphological changes with progestogens vary from suppression of endometrial glandular growth, through stromal decidualization and leukocytic infiltration to glandular atrophy and stromal focal necrosis. In a minority of cases resulting from very prolonged treatment connective tissue fibers increase to some degree and may be accompanied by endometrial fibrosis and calcification. Clinical and histological data have demonstrated that all these changes, including fibrosis and calcification, return to normal in a short period after discontinuing treatment. Endometrial changes during progestogen therapy are often accompanied by leukocyte infiltration, especially when necrosis occurs. White blood cells constitute an important component of normal endometrium. The number and the type of leukocytes change during the normal menstrual cycle apparently related to circulating ovarian hormonal changes. Exogenous progestogens also influence white blood cells, by increasing total numbers and certain specific cell types. Changes in endometrial white blood cell function as a consequence of exogenous progestogens are unclear, but it is possible that the increase of leukocyte infiltration resulting from exogenous progestogens plays an important role in evoking progestational endometrial necrosis.

Effect of mifepristone on inhibition of ovulation and induction of luteolysis.

Mifepristone administration to women in the mid- or late follicular phase delays the luteinizing hormone (LH) surge and prolongs the follicular phase. Since the resumption of follicular growth commences following mifepristone cessation, the drug must be given either continuously or at repeated intervals in order to block ovulation. Using various regimens with or without exogenous progestins, ovulation was inhibited in the majority of subjects. However, this was not consistent and in several instances, LH surges and a rise in plasma progesterone were suggestive of ovulation and corpus luteum function. Therefore, mifepristone cannot be used as a contraceptive which will reliably inhibit ovulation. With low-dose mifepristone administration, alterations in endometrial morphology were characterized by a delay in maturation despite the presence of ovulation. This suggests that the endometrium displays a greater sensitivity to mifepristone than does the pituitary, a finding that may have important contraceptive implications. Late luteal-phase mifepristone administration to women who were not sexually active did not alter their menstrual rhythm, bleeding patterns or steroid and gonadotrophin concentrations. However, when used in unprotected women in the late luteal phase, mifepristone did not uniformly terminate all pregnancies. On the other hand, when used within 72 h of intercourse, mifepristone was as effective a post-coital agent as the standard high-dose oestrogen-progestin combination.

Unanswered questions in hormonal replacement therapy

This review addresses many of the unanswered questions existing relative to the use of exogenous estrogens and progestins in postmenopausal women (PMW). The literature in the field is reviewed and summarized, with a particular effort to identify key questions of major concern. The effect of selection bias on conclusions reached from retrospective studies involving hormone replacement therapy (HRT) has not been examined. Less is actually known about the effects of progestins than estrogens. Many of the endocrine changes that occur with aging remain poorly defined. Effects of estrogens and progestins on the breast and on breast cancer are unclear. Estrogens have recognized beneficial effects and progestins have detrimental effects on lipoprotein metabolism. Estrogens also have direct effects on the vasculature and may impact on cardiovascular risk in other ways. Although estrogens are the only agents known to eliminate hot flushes, the mechanism by which flushes arise is not known. Estrogens may have ameliorating effects on mood and behavior and may improve dementia, but research in this area has been limited to date. Lastly, the preferred estrogens and progestins, their dosages and routes of administration, remain to be more completely defined.

Resumption of Follicular Activity and Interval to Postpartum Ovulation After Exogenous Progestins

In Experiment 1, treatment of dairy cows with progesterone using an intravaginal device from d 5 to 15 postpartum failed to alter onset or duration of the first estrous cycle. Compared with controls in Experiment 2, concentrations of FSH increased, and those of LH decreased, in cows treated with either norgestomet or progesterone for 6 d. Relationships of various measures of LH, but not FSH, were all positive with increasing days postpartum, and those of FSH produced positive polynomial regressions as days to first ovulation decreased. No significant changes in follicular status occurred during or after progestin treatments; however, a consistent relationship was observed between increasing diameter of dominant follicles and serum concentrations of estradiol-17β in most cows. Appearance of the ovulatory dominant follicle generally was detected 4 to 5 d before ovulation regardless of treatment and was first detected more frequently during treatment with progestins when concentrations of FSH were increased compared with controls. Concentrations of progesterone were higher on d 7 to 10 following removal of progestin treatments. Appearance of the first dominant follicle was detected during periods of increased average minimum concentrations of FSH, increased variation in LH secretion, and was related to subsequent duration of the first estrous cycle.

Effects of the anti-progestin and anti-glucocorticoid steroid RU486 on cell proliferation in oviductal embryos of lactating mice

The effects of the progestin and glucocorticoid antagonist RU486 on cleavage rate of oviductal embryos from lactating mice was studied. Preliminary experiments suggested that, owing to suppression of follicular activity by lactation, the effects of RU486 during early embryo development could be studied independently of overt oestrogen dominance in mice mated at postpartum oestrus. After treatment with RU486 on days 1-3 of pregnancy in lactating mice, embryos recovered on day 4, but not on day 3, had significantly fewer cells than did those from control animals. However, neither exogenous progestins nor dexamethasone could reverse this effect of RU486. Nevertheless, embryos recovered from lactating mice treated with progestins alone had significantly more cells on day 4 than did those from control animals. In contrast, embryos recovered from mice treated with dexamethasone alone had significantly fewer cells per embryo on day 4 than did those from control mice. These results provide further evidence that the growth rate of oviductal embryos in mice is influenced by the maternal hormone milieu.

Relationship of progesterone to early pregnancy loss in mares

Exogenous progestins are often given to pregnant mares but many questions remain unanswered as to the relationship between concentrations of progesterone and embryo survival. Thus, embryos were collected 7 days after ovulation and transferred into either ovarian-intact recipients (I,n=15) or ovariectomized recipients which were given 100 mg progesterone (L,n=15) or 1,500 mg progesterone (H,n=15) daily. Concentrations of progesterone were determined in all mares from days 0 to 13. Recipients were examined for pregnancy with ultrasonography during days 11 through 25. Between days 28 and 100, twelve ovarian-intact, pregnant recipients were monitored for follicular and luteal changes and bled for determination of progesterone concentrations for 4 days at 2-week intervals. Twelve ovariectomized pregnant recipients were taken off injectable progesterone days 25-30 and pregnancy maintained to day 100 with an oral progestin, altrenogest. Concentrations of progesterone in these mares were determined every 3 days. Progesterone treatment had no effect on maintenance of pregnancy to day 100 or size of embryonic vesicle (P>0.05). Levels of progesterone during days 1 to 13 were 1.3 to 3.0 ng/ml, >25 ng/ml and 7 to 9 ng/ml for groups L, H and I, respectively. Concentrations of endogenous progesterone in ovariectomized pregnant mares became >1 ng/ml by day 91 of gestation indicating placental progesterone secretion. Increased concentrations of progesterone from days 60 to 100, seen in ovarian-intact, pregnant mares, were primarily due to secretions from corpora lutea. There was, in fact, a correlation between the number of 2°CL and progesterone level (r2=0.74). Initial formation of secondary CL's (2°CL) occurred from 28 to 51 days, with peak formation of 2°CL on days 55 to 70 of gestation.

Exogenous Progestins and Breast Cancer

More research on the effect of exogenous progestins on breast cancer risk is clearly needed. Biologic evidence that progestins may act synergistically with estrogen to enhance proliferation of breast epithelial cells emphasizes the importance of further exploration of this issue, particularly given the increasing prevalence of exposure to contraceptive and noncontraceptive progestins. No specific type or dose of progestin in monophasic combination oral contraceptives has been linked to breast cancer. Based on the few epidemiologic studies of progestin-only oral contraceptives, there also is no evidence that they increase risk of breast cancer. Two studies found that longer-term use of progestin-only pills was associated with a decreased risk of breast cancer. However, given the low prevalence of use of minipills, it is unlikely that this exposure substantially affects the incidence of breast cancer in the population as a whole. Use of the injectable contraceptive DMPA has been positively associated with risk of breast cancer in some subgroups of women, although no significant overall adverse effect has been observed in the two largest studies conducted to date. There is suggestive evidence that use at an early age or prior to a first term birth and recent use may increase risk of breast cancer. It remains unclear, however, whether or not surveillance bias may explain the positive association observed in recent users. Additional research on DMPA and breast cancer incidence is needed, since studies published to date have lacked sufficient power to evaluate risk in relation to long-term use. Future studies of breast cancer in relation to use of other long-acting progestational agents such as Norplant will also be important. There is concern about the relation between breast cancer incidence and use of combined estrogen-progestin replacement therapy, especially extended periods of use. At the present time, only one study (45) has estimated risk according to duration of use, and it remains uncertain whether the reported elevation in risk seen in long-term users of combined therapy is due to enhanced surveillance for breast cancer among exposed women. Further research will be required before any definitive conclusions can be reached about the potential effect of estrogen-progestin replacement regimens on breast cancer incidence. Future studies should attempt to determine the circumstances under which progestins may alter risk of breast cancer and whether such effects vary by duration of use, dosage, type of preparation, concomitant use of estrogens, regimen of exposure, and the timing of progestin use in relation to age and menstrual and reproductive events.(ABSTRACT TRUNCATED AT 400 WORDS)

Exogenous progesterone and progestins as used in estrous synchrony regimens do not mimic the corpus luteum in regulation of luteinizing hormone and 17 beta-estradiol in circulation of cows.

Our working hypothesis was that the low concentrations of progesterone (P4) and synthetic progestins administered in hormonal regimens to control estrous cycles of cows would have similar effects on secretion of LH and 17 beta-estradiol (E2). In addition, we hypothesized that concentrations of exogenous P4 typical of the midluteal phase of the estrous cycle and the corpus luteum (CL) would have similar effects on LH and E2, and the effects would be different from those of synthetic progestins and low concentrations of P4. Cows (n = 29) were randomly assigned to one of five treatment groups: 1) one Progesterone Releasing Intravaginal Device (1PRID; n = 6); 2) two PRIDs (2PRID; n = 6); 3) norgestomet, as in Syncro-Mate-B regimen (SMB; n = 6); 4) melengestrol acetate (MGA; 0.5 mg/day; n = 5); and 5) control (CONT; n = 6). Treatments were administered for 9 days (Day 0 = initiation of treatment). All cows from 1PRID, 2PRID, SMB, and MGA groups were injected with prostaglandin F2 alpha (PGF2 alpha) on Days 2 and 5 of the treatment period to regress CL. Cows in the 1PRID and SMB groups were also administered exogenous estrogen according to the respective estrous synchronization protocol for these products. Daily blood samples were collected from Day 0 to 35 to determine concentrations of P4. On Day 8, blood samples were collected at 15-min intervals for 24 h to determine pattern of LH secretion. On Day 9, all treatments ceased and cows in the CONT group received injections of PGF2 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory stimulation by female hormones in awake male rats

The respiratory effect of progestin differs among various animal species and humans. The rat does not hyperventilate in response to exogenous progestin. The present study was conducted to determine whether administration of combined progestin and estrogen prompts ventilatory stimulation in the male rat. Ventilation, blood gases, and metabolic rates (O2 consumption and CO2 production) were measured in the awake and unrestrained male Wistar rat. The combined administration of a synthetic potent progestin (TZP4238) and estradiol for 5 days significantly increased tidal volume and minute expiratory ventilation (VE), reduced arterial PCO2, and enhanced the ventilatory response to CO2 inhalation (delta VE/delta PCO2). On the other hand, respiratory frequency, O2 consumption, CO2 production, and body temperature were not affected. The arterial pH increased slightly, with a concomitant decrease in plasma [HCO3-]. Administration of either TZP4238 or estradiol alone or vehicle (Tween 80) had no effect on respiration, blood gases, and ventilatory response to CO2. The results indicated that respiratory stimulation following combined progestin plus estradiol treatment in the male rat involves activation of process(es) that regulate tidal volume and its augmentation during CO2 stimulus.