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There are hormones from 2 sources which determine the menstrual cycle. The pituitary produces luteinizing hormone and follicle stimulating hormone and the ovaries secrete estrogen and progesterone. For clinical use, a cheap source of progesterone has been found in the Mexican yam. Since the 1st oral contraceptives were tested in Puerto Rico in the late 1950s, there has been a trend toward reducing the dosage. Estrogen prevents ovulation in 95-98% of patients. Other factors are also involved. Although it is estimated that 80-100 million women in the world today use oral contraceptives, this method is not always followed for long periods. From 25 to 60% discontinue the use within the 1st year. Increased risk of unfavorable side effects occurs in those with high blood pressure, migraine headaches, diabetes, epilepsy, undiagnosed genital bleeding, or gallbladder disease. Women over age 40 run a greater risk of heart attacks. Intravenous blood clots are the major risk. Severe abdominal, chest, or leg pains, severe headaches, and eye problems may be symptoms of blood clots. With the 21-day package the user takes a pill a day for 3 weeks and then none during menstruation. The sequential type of medication is no longer used. Minipills are taken every day. Missing taking pills is the most common cause of failure of the method. Estrogen replacement therapy for menopausal women is a temporary treatment to relieve physical distress. Depo-Provera, containing a long-acting progesterone agent, may be injected every 3 months instead of daily oral contraceptives. When progesterone is used with an IUD it acts locally. Hormones to maintain pregnancy are no longer used. Use of hormones as a test for pregnancy has been discontinued. Estrogen-progesterone injections given to inhibit milk production may cause serious side effects.
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PMID:The pills: oral contraceptives and other hormones. 1230 26

Contraceptive practice guidelines have the potential to assist health care providers in evaluating the needs and expectations of women seeking contraception, educating patients, and monitoring successful contraceptive use. This article presents guidelines for IUD patient selection developed by several members of the editorial board of the US newsletter, "Dialogues in Contraception." Misinformation about the IUD has prevented many clinicians and patients from considering this method, despite recent improvements in its design. The currently available data suggest that the two IUDs available in the US, Copper T 380A and Progestasert, cause a local reaction that is toxic to sperm (and perhaps ova), thereby preventing fertilization. Modern IUDs, which use only monofilament tails, do not increase the risk of pelvic inflammatory disease in women without evidence of lower genital tract infection. Beyond avoiding women at risk for sexually transmitted diseases, there are few barriers to IUD use. The method is appropriate for women who are contemplating but ambivalent about sterilization, aged under 25 years, perimenopausal, nulliparous or parous, postpartum or postabortion, lactating, and cigarette smokers over 35 years of age. Contraindications to IUD use are postpregnancy infection, unresolved acute cervicitis or vaginitis, distorted uterine cavity, uterine or cervical cancer, unexplained abnormal vaginal bleeding, increased susceptibility to infection, genital actinomycosis, immunocompromised patients, and diabetes mellitus (progesterone-releasing IUD only).
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PMID:IUD patient selection and practice guidelines. 1232 91

This "Ask the Experts" column addresses two concerns related to use of Depo-Provera. The first question relates to the clinical significance of frequent urination. Two of the three experts assert that frequent urination in a Depo-Provera user is unlikely to be related to method use; urinary tract infection and diabetes are more probable causes. The third notes that hypoestrogenicity could be a factor and suggests examination of the vagina for atrophy, which could cause the tissue around the urethra to become atrophic. The second question addresses techniques for confirming menopause in Depo-Provera users. The experts concur that measurement of follicle-stimulating hormone in perimenopausal Depo-Provera users lacks predictive value. Recommended, instead, is continuation of Depo-Provera with supplemental estrogen until the woman is in her mid-50s. At that time, conventional hormone replacement therapy can be initiated.
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PMID:Frequent urination and Depo-Provera. Ask the experts. 1232 8

About 600 injections per year are administered in a Luxembourg family planning center using 3 types of long acting progestatives: Depo Provera 150 and 450 and Norigest. The method is no longer reserved for women with completed families and the mentally handicapped since its reversibility has been proven. Patients seeking this type of contraception must meet the same criteria as for oral contraceptives except that women with contraindications for estrogens may tolerate progestatives. Long acting progestatives offer the safety of minipills along with high effectiveness since the risk of forgetting a pill is removed. Some women with cardiac disease, diabetes, and circulatory problems are able to use injectables, but caution should be exercised with hypertensives and the obese because of possible weight gain. Women with coagulation problems or suspected fibromas should be excluded. Administered postpartum, pure progestatives do not affect lactation. Menstrual cycles are completely disturbed, with irregular and unpredictable bleeding until amenorrhea appears after 3-6 months. Women who are psychologically unable to accept amenorrhea should not use this method, as they are more likely to experience undesirable side effects. Return of fertility upon termination of use poses no problem and usually occurs after 6-10 months, even after a single injection. Treatment with a sequential contraceptive beginning on the day when the next injection would have been given may help to reestablish menstruation. The physician should determine through a preliminary interview the couple's psychological readiness for this type of contraception. A careful medical history and gynecological examination should be done to rule out contraindications, and treatment should begin in the 1st 3 days of the cycle. Irregular and prolonged bleeding after 6 months of use can be treated with oral administration of estrogen, or by proceeding to the next injection ahead of schedule. Administration of a mild diuretic is rarely necessary for water retention. Pregnancy during use of the method is very rare but usually occurs after the 2nd or 3rd treatment and may be detected only in the 3rd or 4th month. Uterine size should be assessed at each treatment for the 1st year. Short term local treatment with estrogen rapidly restores vaginal lubrication when necessary. No serious incidents have occurred with use of long acting progestatives at this clinic.
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PMID:[Indications and medical survey of long acting progestatives used for contraception (author's transl)]. 1233 49

In this article, Dr. Andrew M. Kaunitz, associate professor of obstetrics and gynecology at the University of Florida Health Sciences Center in Jacksonville, gives suggestions for prescribing Depo-Provera. While Depo-Provera works as a contraceptive primarily by inhibiting ovulation, it has other antifertility effects, such as endometrial atrophy and cervical mucus thickening, which help prevent pregnancy in case ovulation does occur. A usual dose of Depo-Provera, 150 mg given intramuscularly every 3 months, has a contraceptive efficacy rate of 99.6%--the highest rate for any hormonal method. Kaunitz explains that the initial injection of the drug should take place within 7 days of the beginning of menses to ensure that there is no pregnancy. Efficacy is highest up to 12 weeks after injection, even though ovulation does not take place 14 weeks after the drug is administered. In the event that the patient is more than 2 weeks late in receiving her second or subsequent injection, Kaunitz recommends obtaining a pregnancy test. Because of possible adverse effects on carbohydrate metabolism and lipoprotein levels, Kaunitz suggests that women at high risk of cardiovascular disease or diabetes receive a lower dose of the drug, 100 mg. Similarly, very small women (those weighing under 100 lbs) may also require a smaller dose. Even at a lower dose, says Kaunitz, Depo-Provera remains highly effective, with a failure rate of 1%. Kaunitz also emphasizes prescribing Depo-Provera only to women who want a long-term contraceptive (at least 2 years), since although it does not affect fertility permanently, it does take longer for fertility to return than with oral contraceptives or Norplant.
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PMID:Prescribing tips for Depo-Provera. 1234 62

The bulk of the experimental data suggest beneficial effects of estrogen (both premenopausal use of OCs and postmenopausal use of ERT-HRT). An intriguing finding from the monkey studies is that social subordination, which induces estrogen deficiency in female monkeys, accelerates atherosclerosis premenopausally and predicts extent of postmenopausal atherosclerosis. This effect can be inhibited by exogenous estrogen, premenopausally. The results suggest that more effort on detecting and regulating premenopausal ovarian dysfunction may be justified. A complication in understanding estrogen action may be the result of varying extents of arterial damage. For example, primary prevention studies in both postmenopausal animals and women have provided strong evidence of atheroprotection with a variety of estrogens. In contrast, the results of secondary prevention studies [10,12] have in general suggested little cardioprotection with either ERT or HRT. Studies in rabbits suggest the antiatherogenic effect of estrogen may not be present when the endothelium is damaged [64]. The state of the endothelium may be critical for some estrogen actions. For those effects of estrogen that require the ER, be it ERalpha or ERbeta, the presence of the receptor may vary with age, disease state, or type of hormone therapy. If continuous combined HRT therapy decreases ER in the artery as it does in the uterus, this may eliminate those estrogen actions requiring the ER, but not others. Older women who have not been exposed to estrogens for many years may be more sensitive to some estrogen effects, and may need lower doses of ERT-HRT. Recent reports suggest that lower doses of estrogens maintain beneficial effects on lipoproteins and coagulation factors [95], while also requiring lower doses of progestogens to protect the uterus [96]. These beneficial findings are very promising in light of the improvements in CHD risk and decreased stroke risk reported with low-dose estrogens [5]. It ill be interesting to see if CRP is increased with lower doses of estrogens and whether these changes are associated with increased early risk of CHD. Perhaps older women with CHD are also more obese, may have diabetes, and may be more susceptible to inflammatory and thrombotic effects of higher doses of estrogens. There are many questions left unanswered. It is hoped that some of the answers may come from the WHI, which is a large prospective trial assessing ERT and HRT. The age range is also relatively large and may be able to determine if older women respond differently than younger women. Some initial data from the WHI have been made available suggesting a small increased risk in the first 2 years and a trend for decreasing risk in the last months of the first 2 years [34]. Just recently, the CEE + MPA arm of the study was stopped early by the data and-safety monitoring board as the overall health risks exceeded benefits with increases in both breast cancer and CVD [97]. The remainder of the study groups including an estrogen-only arm, are expected to continue until 2005.
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PMID:Reproductive hormones and cardiovascular disease mechanism of action and clinical implications. 1235 69

MAP (mitogen-activated protein) kinase (also called Erk 1/2) plays a crucial role in cell proliferation and differentiation. Its impact on secretory events is less well established. The interplay of protein kinase C (PKC), PI3-kinase and cellular tyrosine kinase with MAP kinase activity using inhibitors and compounds such as glucose, phorbol 12-myristate 13-acetate (PMA) and agonists of G-protein coupled receptors like gastrin releasing peptide (GRP), oxytocin (OT) and glucose-dependent insulinotropic peptide (GIP) was investigated in INS-1 cells, an insulin secreting cell line. MAP kinase activity was determined by using a peptide derived from the EGF receptor as a MAP kinase substrate and [32P]ATP. Glucose as well as GRP, OT and GIP exhibited a time-dependent increase in MAP kinase activity with a maximum at time point 2.5 min. All further experiments were performed using 2.5 min incubations. The flavone PD 098059 is known to bind to the inactive forms of MEK1 (MAPK/ERK-Kinase) thus preventing activation by upstream activators. 20 microM PD 098059 (IC50 = 5 microM) inhibited MAP kinase stimulated by either glucose, GRP, OT, GIP or PMA. Inhibiton ("downregulation") of PKC by a long term (22 h) pretreatment with 1 microM PMA did not influence MAP kinase activity when augmented by either of the above mentioned compound. To investigate whether PI3-kinase and cellular tyrosine kinase are involved in G-protein mediated effects on MAP kinase, inhibitors were used: 100 nM wortmannin (PI3-kinase inhibitor) reduced the effects of GRP, OT and GIP but not that of PMA; 100 microM genistein (tyrosine kinase inhibitor) inhibited the stimulatory effect of either above mentioned compound on MAP kinase activation. Inhibition of MAP kinase by 20 microM PD 098059 did not influence insulin secretion modulated by either compound (glucose, GRP, OT or GIP). [3H]Thymidine incorporation, however, was severely inhibited by PD 098059. Thus MAP kinase is important for INS-1 cell proliferation but not for its insulin secretory response with respect to major initiators and modulators of insulin release. The data indicate that MAP kinase is active and under the control of MAP kinase. PKC is upstream of a genistein-sensitive tyrosine kinase and probably downstream of a PI3-kinase in INS-1 cells.
Int J Exp Diabetes Res 2001
PMID:Role of protein kinase C, PI3-kinase and tyrosine kinase in activation of MAP kinase by glucose and agonists of G-protein coupled receptors in INS-1 cells. 1236 12

We examined the hypothesis that gender differences exist in platelet and vascular reactivity in type-2 diabetes mellitus, using Zucker fatty diabetic rats of both sexes and their lean littermates. Type-2 diabetes is characterized by excessive platelet production of TXA(2), which is thrombogenic. Testosterone up-regulates platelet TXA(2) receptors and the aggregation response to thromboxane mimetics. Conversely, estrogen increases vascular nitric oxide (NO) production and inhibits platelet aggregation. Hemodynamic studies were undertaken with the determination of dose-response curve for MAP and renal cortical blood flow (RCF) in response to U46619, angiotensin-II, phenylephrine and endothelin-1, as well as the systemic hemodynamic response to acetylcholine and L-NG nitro-arginine methylester (L-NAME). Platelet aggregation response was evaluated using whole blood impedance aggregometry. There were significant gender differences in the systemic blood pressure and RCF response to TXA(2)-mimetic U46619 and angiotensin-II (P<0.02, ANOVA) but not to phenylephrine or endothelin-1. Male rats exhibited a paradoxical hypotensive response to U46619 (-18+/-11 mmHg) compared with a peak pressor response of +6+/-1 mmHg in female rats (P<0.01, ANOVA). The male rats exhibited an attenuated systemic vasodilator response (P<0.001, ANOVA) to acetylcholine (fall in MAP in male diabetic rats being -24+/-8 mmHg, compared with a fall of -50+/-8 mmHg in females), but a greater rise in the renal cortical resistance in response to NO inhibition by L-NAME (P<0.03) compared with the female rats. Both the slope (46+/-2) and the peak magnitude of the U46619-induced whole blood platelet aggregation (13+/-1) ohms were significantly higher (P<0.01, ANOVA) in male (n=10) compared with female diabetic rats (n=8) (29+/-0.8 slope, 10.0+/-0.8 ohms, respectively). Thus, the male diabetic Zucker rats exhibited an impaired response to vasoconstrictors (U46619 and angiotensin-II) and to endothelial (NO)-mediated vasodilation. The male gender may therefore be associated with the greater prothrombotic activity and a worse impairment of endothelial reactivity in the type-2 diabetic state.
Diabetes Res Clin Pract 2003 Jan
PMID:Gender difference in vascular and platelet reactivity to thromboxane A(2)-mimetic U46619 and to endothelial dependent vasodilation in Zucker fatty (hypertensive, hyperinsulinemic) diabetic rats. 1248 37

Progestin-only contraceptives administered by injection (Depo-Provera) or subcutaneous implant (Norplant) have been available to U.S. women for about a decade. Two epidemiological studies found their use associated with increased incidence of type 2 diabetes. In reviewing publications relating progestin injections and implants to glucose metabolism, 25 studies of various study designs and laboratory methods were identified that reported at least one insulin value in nondiabetic women. Research subjects were usually nonobese and often from developing countries. Of eight studies that performed sequential oral glucose tolerance tests (OGTTs) after at least 6 months of Depo-Provera or Norplant use, seven found significant elevations (approximate doubling) of insulin at 2 or 3 h after glucose challenge; the effects on fasting, half-hour, or 1-h postchallenge insulin values were less consistent. The three studies that performed sequential intravenous glucose tolerance tests (IVGTTs) on injection users all found an increased early-phase insulin response. One study used sequential hyperglycemic-hyperinsulinemic clamps to demonstrate reduced total-body glucose uptake per unit of insulin after 8 weeks of Norplant use. The metabolic studies generally did not show a reduction in the glucose tolerance of their nondiabetic subjects. However, compared with the lean and low-risk women who were usually selected for metabolic research, many U.S. women receiving these injections or implants may start out with increased insulin resistance due to greater weight, sedentary lifestyle, and family or childbearing histories. Additional research could help clarify whether exposure to injectable or implantable contraceptives leads to increased risk of type 2 diabetes and gestational diabetes in women with predisposing factors.
Diabetes Care 2003 Jan
PMID:Effects of injectable or implantable progestin-only contraceptives on insulin-glucose metabolism and diabetes risk. 1250 84

Insulin resistance is one of the metabolic changes in pregnancy, but only a fraction of women develop overt impaired glucose tolerance or frank diabetes. Most women are able to compensate this altered metabolic state by increasing the amount of insulin produced by the pancreatic beta cells. Progesterone might well be the key to the development of gestational diabetes. Previously high progesterone levels have already been shown to be correlated with the development of glucose abnormalities in pregnancy and now, in a new paper, progesterone receptor-knockout mice are found to have improved glucose tolerance. These mice showed increased insulin secretion, which is probably linked to the presence of increased numbers of beta cells in their pancreas. Is progesterone therefore the 'ultimate bad guy', prohibiting normal adaptation of the pancreatic beta-cell reserve during pregnancy?
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PMID:Progesterone in gestational diabetes mellitus: guilty or not guilty? 1259 Nov 70


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