Controversial abortifacient (used to induce abortions)
Binds both progesterone and glucocorticoid receptors - preventing gene transcription
Also very good antagonist at glucocorticoid receptor but its typical used to block progesterone receptor
Other potential therapeutic uses:
Inhibition of progesterone- and glucocorticoid-dependent tumors
Effective in treatment of fibroid tumors
Post-coital birth control—better ways of achieving this now
CONTROL OF IMPLANTATION BY PROGESTERONE AND HCG
RU486 causes breakdown of the endometrial layer because the progesterone cannot be stimulated to maintain it and once that endometrial layer starts to break down you get partial detachment of the embryo and viability of the embryonic cells starts to and its ability to produce hCG also which leads to maintenance of the CL (which is producing endogenous progesterone) so this also acts to progesterone. With P you also get breakdown of endometrial layer and enhanced uterine contractility b/c now PG can be secreted and these contraction combined w/ the partial detachment due to atrophy of the endometrium leads to complete detachment and expulsion of the embryo. You also get a softening and dilation of the cervix Most serious side effect of this treatment is BLEEDING which can be sufficient enough to cause death.
Early stages of implantation and development. Trophoblasts cells that go on to form the placenta are growing very rapidly and producing hCG to signal to the CL to continue to making progesterone so the endometrial layer is maintained for development. Progesterone supports the secretory endometrium, it also inhibits the contractility of the uterine muscle by inhibiting the production and secretion of PG’s, and it firms the cervix and inhibits the dilation of it.
ABORTIFACIENT ACTIONS OF RU486
RU486 alone: 400-600 mg/day (oral) for 4 days = 85% effective –no longer used these days
RU486 (600 mg) + Prostaglandin E1 (to contractions) = 95% effective preferred use of this
“Plan B” drug (L-NORGESTREL) approved by FDA in 1999; as over-the-counter drug to adults in 2009.
Effectiveness: 89% (72 hours), 95% (24 hours)
Mechanism – Delays ovulation and sperm migration, found not to disrupt implantation
Remember these are not true progestational agents—they don't support the secretory phase of the endometrium so now the sperm have a hard time migrating up the uterus and fallopian tubes to get to the egg
In women who have ovulated Plan B has no protective effect b/c it doesn't block implantation or fertilization of egg
Strong side effects –these are minimized w/ Plan B though
COMBINED ORAL CONTRACEPTIVES (COCS)
Constant dose of estrogen + progestin over 21 days
Diphasic and triphasic—these were developed to deal with the problem of irregular spotting associated with the monophasic approach
Constant low dose of estrogen + variable dose of progestin
Diphasic: progestin dose increased once at approx. day 10, higher dose maintained to day 21.
Somewhere in the middle you the dose of progestin
Usually not life-threatening - unless adenoma ruptures
Cervical and Vaginal Cancer
Clear risk due to use of diethylstilbestrol (DES)
Risk only for daughters of women who used DES during 1st trimester of pregnancy—this is a historical problem—doctors prescribed it for women who wanted to get pregnant which is not what it does!
Controversial. Most studies show increased risk.
Endometrial and Ovarian Cancers
Several studies show 2-15X risk of endometrial cancer for estrogen-alone therapies
Clear evidence that risks of endometrial and ovarian cancers decrease in women taking COCs
COCs resulted in 2-fold protection against endometrial (12 vs 23 per 100,000) and ovarian cancer (18 vs 30 per 100,000)
Magnitude of protection constant with age (35+ years)
“Hormonal Chemoprevention of Cancer in Women” Henderson et al, Science 259: 633 (1993)
showed that it is the Progestin that is protective against these cancers b/c remember P stimulates rapidly growing endometrial cells to stop rapidly growing and differentiating cause the endometrium to go into the secretory phase. P blocks E growth properties on the endometrium.
SIDE EFFECTS OF ESTROGEN REPLACEMENT THERAPY (ERT)
Bottom Line? ERT only for moderate to severe symptoms of menopause (hot flashes and night sweats) and as second-line drug for prevention of osteoporosis (when bisphosphonates don't work)
Side Effects of the WHI Study
“What happened is that medical practice, as it often does, got ahead of medical science. We made observations and developed hypotheses – and forgot to prove them.” Susan M. Love, NY Times, July 16, 2002
Produced in testis, ovary and adrenals
Produced in Leydig cells of testis
Converted to Dihydroxytestosterone (DHT) by Sertoli cells and other target tissues
Separation of anabolic and androgenic effects not as effective in humans
In female athletes
Marked increase in muscle mass, strength and aggressiveness (highly anabolic in women)
Acute “masculinization” - hirsutism, deep voice, depressed menses
In male athletes: questionable efficacy? The level of training these athletes undergo probably has more to do with the in muscle mass they see than the anabolic steroids themselves
In both sexes: danger of liver disease (jaundice) etc.
Many early studies “failed” to find effective male contraceptive
Due in part to over-emphasis on azoospermia
Notion was only takes one sperm to fertilize an egg and the male produces millions and millions of sperm the only way to achieve effective contraception in men is to get them down to producing NO SPERM but that's not necessarily true
New studies suggest that critical threshold is 3 X 106 sperm per ejaculation—below that is considered infertile
B/c testosterone production is controlled by the same HP axis as women
100% effective in small trial
NSAIDS AND OTHER ANTI-INFLAMMATORY DRUGS
SIMPLIFIED MODEL OF RHEUMATOID ARTHRITIS
Bone is covered in cartilage to wear and tear on the bone and to the wear and tear on the cartilage the joint itself is encased in synovial membrane which secretes synovial fluid which acts like an oil to wear and tear on cartilage.
RA is an autoimmune disease in which antibodies against self-proteins are generated
Macrophages (M) engulf antigens that pass to lymph nodes and present peptides to T-cells leading to T-cell activation and proliferation. Requires interleukin-1 (IL-1) produced by macrophage and induction of IL-2 production by T-cells—IL-2 is important for T cell proliferation
Activated, type 1 helper TH1-cells pass through blood to inflamed tissue, where they activate M that present the appropriate antigen - a process involving release of IFN γ
Activated M release TNF and IL-1, cause expression of adhesions proteins which attract other cells to the site which activate other M, fibroblasts and osteoclasts, and growth factors that promote angiogenesis (supply growing pannus)
Fibroblasts and osteoclasts especially start to secrete collagenases which start to break down cartilage and osteoclasts break down bone
Prostaglandins, leukotrienes and NO released by M lead to vasodilation, and increased vascular permeability
TNF promote entry of WBCs from blood, e.g. by inducing expression of VCAM-1. “Pannus” –is swelling of synovial membrane thickened by infiltration of T cells, macrophages, fibroblasts- develops at junction of synovial membrane and cartilage
Matrix metalloproteinases (MMPs) released from activated macrophages and fibroblasts break down cartilage
Activated osteoclasts promote breakdown of bone
Net result joint damage and deformation
Sites of Action of Anti-inflammatory Drugs. TNF binds to its receptor and activates a kinase (IBK) which phosphorylates the inhibitory protein IB, which is then degraded. NFB is then free to enter the nucleus and activate expression of various genes.
-Zileuton was an important drug for asthma and now RA because it inhibits 5’-LO which makes LT’s. Zafirlukast is an antagonist of LT so it also is important in asthma and allergies but not indicated for RA. Most important anti-inflamm drugs are glucocorticoids (stim production of IkB as well as other things)
TNF plays a key role in propagating inflammation. TNF is a protein produced by macrophages following stimulation by various agents, e.g. lipopolysaccharide (LPS, or endotoxin) produced by gram-negative bacteria. TNF binds to specific receptors on a variety of cell types and activates a transcription factor called nuclear factor B (NF-B), which enters the nucleus and switches on the synthesis of many proinflammatory proteins.
Cyclooxygenase 2 (Cox-2))
5’-Lipoxygenase (5’LO) and its activator protein-FLAP
TNF and interleukin-1 (IL-1) to amplify and propagate the process
Activation of NF-B occurs when its inhibitor, a protein called I-B, is phosphorylated by a specific protein kinase (I-B kinase, IKK) and degraded. The net effect is an increased synthesis of prostaglandins and leukotrienes
TNF binds to its receptors and will activate a kinase which will phosphorylate IkB which inactivates it and released NFkB to go into the nucleus and turn on synthesis of proteins which drive inflammation—this causes more cytokines to be released and these inflammatory processes will result in the synthesis of PLA2 which releases arachadonic acid causing the synthesis of COX2 that generates the prostaglandins. Also induces the synthesis of 5’-Lipoxygenase which leads to leukotriene production. Inducible NOS gets activated and you get NO. To keep the inflammatory processes in control we have other actions like these cells produce IL-1 receptor antagonists so that will moderate effects on IL-1. Also produce other receptors for TNF, which gets cleaved from the membrane making them soluble receptors and these are receptors obviously for TNF and if its bound to a soluble receptor it is not activating the cell so this will TNF effects. Most importantly It induced IkB inhibitory protein which will block NFkB effects in the nucleus.