Table of contents :

• GH excess
• SST₁ agonists
• SST₂ agonists
• SST₃ agonists
• SST₄ agonists
• SST₅ agonists
• D₂ agonists :
• bromocriptine : 1 cps a day (gastrointestinal side effects)
• cabergoline : 1/2 cps 2 times a week
• GH-R antagonists
• PRL excess
• D₂ agonists
• LH and FSH deficiencies (including short children with precocious puberty)
• GnRH-R agonists
• Induction, aumentation, and third stage of labor
• OT-R antagonists
• natural and semisynthetic ergot alkaloids
• hyperthyroidism
• antithyroid drugs
• TPo inhibitors. Side effects : agranulocytosis, aplastic anemia
• hormone release inhibitors
• thyroid deiodinase inhibitors
• NIS blockers
• high concentrations of iodine cause generation of organic iodocompounds within the thyroid => decrease in NIS mRNA and protein => decrease proteolytic release of iodothyronines from thyroglobulin => slowing of thyroid hormone secretion (Wolff-Chaikoff effect). This effect is exploited in the treatment of thyrotoxic crisis or severe thyrocardiac disease. Iodine also reduces thyroid cellularity and vascularity and therefore is used in the preparation of the patient for thyroidectomy. Finally, by exploiting the failure of escape from the Wolff-Chaikoff effect, iodine may also be used in the early management of radioiodine-treated Graves' diseases.

Commonly used iodine-containing drugs are :
• oral or local
• amiodarone
• calcium iodide (Calcidrine Syrup^®)
• iodoquinol / diiodohydroxyquin
• echothiophate iodide ophthalmic solution
• hydriodic acid syrup
• iodine-containing vitamins
• niacinamide hydroiodide + potassium iodide (Iodo-Niacin^®)
• iduxuridine ophthalmic solution
• kelp
• potassium iodide (Quadrinal^®)
• Lugol's solution
• Ponaris^® nasal emollient
• saturated solution of potassium iodide
• parenteral preparations
• sodium iodide, 10% solution
• iodine-based topical antiseptics
• iodinated radiology contrast agents
• adjuvant drugs
• b-AR antagonists to antagonize the catecholaminergic effects of thyrotoxicosis
• L-type voltage-gated Ca²⁺ channel blockers to control tachycardias and decrease the incidence of supraventricular tachyarrhythmias
• cholestyramine binds thyroid hormones in the gut preventing enterohepatic recirculation
• secondary hyperparathyroidism: CASR agonists
• Hypothalamus-pituitary-adrenal (HPA) axis
• GR agonists and antagonists
• CYP11A inhibitors
• CYP11B1 / steroid 11b-hydroxylase inhibitors
• 3b-hydroxysteroid dehydrogenase inhibitors
• CYP17A1 / P450_17a inhibitors
• adrenocorticolytics
• Insulin and glucagon (oral hypoglycemics drugs for diabetes mellitus)

 

		secretagogues				insulin-sensitizing activity
	a-glucosidase inhibitors	ABCC8 / sulfonylurea receptor 1 (SUR1) / KATP inhibitors (sulfonylureas)	GLP1R agonists	SST2 agonists	for liver and skeletal muscles : biguanides activate LKB1–STRADa/b –MO25a/b complexes, which represent the major upstream kinases activating AMPK and  11 other AMPK-related kinases, leading to glucose sequestration and inhibition of cell growth and division, which ultimately prevent tumor development and proliferationref1, ref2. metformin (Devian TM®, Dextin®, Diaberit TM®, Diabetex®, Diabetosan®, Diabex®, Diaformin®, Glucamet®, Glucophage®, Glucophate S®, Mediabet®, Mesorit®, Metforal®, Metiguanide® and Orabet®; extended release : DepoMet®; Glucovance® in combination with glibenclamide; AvandaMet® in combination with rosiglitazone; JanuMet® in combination with sitagliptin) phenformin / phenylethylbiguanide (Chlorformin® in combination with chlorpropamide) buformin	for skeletal muscles : PPARg antagonists (glitazones/thiazolidinedione and glitazars)
reduction in HbA1c	-0.5-1%				- 1-2%
posology	3/day before meals					1/day (prescribed by specialists only)
side effects	flatulence and abdominal tenderness due to bacterial fermentation of unabsorbed polysaccharides, transaminitis	due to activation of ABCC9 / sulfonylurea receptor 2 (SUR2); sudden reversible osmotic lens damage ("sugar cracks") after initiation of metforminref			nausea, diarrhea, parageusia (anorexia is a positive factor for diabetic patients!), lactic acidosis	fast-onset edema in NYHA >= 3; troglitazone may cause hepatocellular carcinoma; lowered PAI, ABP, Glc, FFA, sdLDL, migration and proliferation of monocytes and VSMCs; increased HDL-Ch
body weight	no variation	+ 4-5 kg			-1-2 kg at high doses or none	+ 3-6 kg 8visceral fat
arterial blood pressure	reduced or no variation	no variation			- 4-5%	reduced or no variation
triglycerides	no variation	no variation			- 4-5%	- 1%
T-Ch	no variation	no variation			- 4-5%	+ 15-20%
HDL-Ch	no variation	no variation			no variation	+ 10%
coagulation	no variation	?			reduced	reduced
insulinemia	reduced postprandially	increased			no variation	reduced
insulin resistance	reduced or no variation	no variation			- 5-20%	+ 5-20%

Agents that have appeared promising (by reduction of albuminuria and preservation of kidney function) in phase II studies. To determine whether clinical outcomes (mortality, renal, and cardiovascular events) are improved beyond the current standard of care, phase III trials are planned^ref.
• PKCb inhibitors (ruboxistaurin), a mediator of signal transduction that leads to cell growth, fibrosis, and tissue injury. In diabetes, PKC-beta is up-regulated and activated in the kidney. Ruboxistaurin prevents diabetic kidney disease in animal models^{ref1, ref2}.
• sulodexide (Vessel Due F^®), a mixture of 3 glycosaminoglycans (low-molecular weight heparin and dermatan sulphate), appears to prevent diabetic nephropathy in experimental models by ameliorating abnormalities in the glomerular basement membrane and mesangial matrix.  It has also been shown to inhibit TGF- overexpression and matrix synthesis induced by high concentrations of glucose in mesangial cell to the same extent as the single components and to rectify endothelial dysfunctions observed in DM^{ref1, ref2}
• pyridoxamine is an inhibitor of advanced glycation end-product (AGE) formation derived from vitamin B₆
• alagebrium is an AGE cross-link breaker. AGEs injure the kidneys and other vascular targets by mechanisms such as oxidative stress, inflammation, and protein cross-linking, among others. By inhibiting AGE formation or breaking AGE cross-links, experimental models have demonstrated kidney protection
• Calcification and bone turnover
• VDR agonists
• farnesyl diphosphate (FPP) synthase inhibitors^ref : by inhibiting this enzyme in the osteoclast, bisphosphonates interfere with geranylgeranylation of GTPases required for cytoskeletal organization and vesicular traffic in the osteoclast, leading to osteoclast inactivation.When added to appropriate solutions and sospensions of calcium phosphate, they slow the formation and dissolution of hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂) crystals. Bisphosphonates are ideally suited for the treatment of metabolic bone disease because they bind avidly to the bone mineral at sites of active bone metabolism, where they achieve therapeutic concentrations. The pioneering work of Fleisch and colleagues showed that bisphosphonates not only inhibit dissolution of hydroxyapatite crystals, but also affect osteoclast metabolism and function^{ref1, ref2, ref3}. Bisphosphonates are released during bone resorption and are internalized by osteoclasts, leading to inhibition of bone resorption and induction of osteoclast apoptosis^{ref1, ref2, ref3}. There is now extensive preclinical evidence that bisphosphonates also have antitumor activity, as evidenced by reduced proliferation and viability of tumor cell lines in vitro and reduced skeletal tumor burden and slower progression of bone lesions in animal models. Several mechanisms have been proposed to explain these observations. Bisphosphonates may render the bone a less favorable microenvironment for tumor cell growth by reducing tumor-induced osteolysis and local release of growth factors, and bisphosphonates may also have direct antitumor effects. Bisphosphonates inhibit proliferation and induce apoptosis of a variety of human tumor cell lines in vitro^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8, ref9, ref10, ref11}. Bisphosphonates also inhibit tumor cell adhesion to the extracellular bone matrix, inhibit invasion of tumor cells through Matrigel^TM, and have antiangiogenic and immunomodulatory activities.

Indications :
• management of metastatic cancer in bone (intravenous zoledronic acid or pamidronate)
• prevention and treatment of osteoporosis (oral alendronate, risedronate, and ibandronate and intravenous ibandronate)
• treatment of Paget's disease of bone (intravenous pamidronate and oral alendronate and risedronate)
• short-term management of acute hypercalcemia (intravenous zoledronic acid and pamidronate).
Posology : 1 hour before breakfast for oral route
Side effects :
• upper gastrointestinal intolerance (with oral administration)
• short-lived acute-phase reaction characterized by fever, myalgias, and an influenza-like syndrome (with intravenous administration)
• osteonecrosis of the jaw is characterized clinically by an area of exposed bone in the mandible, maxilla, or palate that typically heals poorly or does not heal over a period of 6 to 8 weeks. The diagnosis is primarily a clinical one, but imaging studies such as computed tomography can be helpful. This condition in connection with bisphosphonate use was first reported in 2003, or 5 to 10 years after these drugs were approved in the USA for their current indications; it was rarely seen before then. Most of the reported cases (95%) have been associated with zoledronic acid or pamidronate given intravenously to control metastatic bone disease^{ref1, ref2}. When these drugs have been administered intravenously in patients with cancer, the reported incidence of osteonecrosis of the jaw has ranged from 1.3% in a preliminary retrospective survey (Hoff AO, Toth B, Altundag K, et al. Osteonecrosis of the jaw in patients receiving intravenous bisphosphonate therapy. J Bone Miner Res 2005;20:Suppl 1:1218-1218) to 4 to 7% in another report^ref. Multiple myeloma and breast carcinoma are by far the most common cancers associated with intravenous bisphosphonate use and osteonecrosis of the jaw^ref. Predisposing factors for the development of osteonecrosis of the jaw appear to be dental disease, dental surgery (e.g., tooth extraction), oral trauma, periodontitis, and poor dental hygiene. Treatment with chemotherapy or corticosteroids is also common among affected patients. The lesion is painful in many, but not all, patients, and infection is often present. Approximately 70% of cases involve the mandible and the rest involve the maxilla. In one unusual case, osteonecrosis of the external auditory canal developed in a patient with myeloma who had received intravenous zoledronic acid and pamidronate^ref. Typically, patients in whom osteonecrosis of the jaw develops have been receiving intravenous bisphosphonate therapy for 1.5 to 3 years. With conservative management (minimal surgical débridement, rinses with cyclohexidine or hydrogen peroxide, antibiotics, and analgesics), the lesions usually heal, although some cases of osteonecrosis of the jaw have become chronic and some patients have had complications. For metastatic cancer, the doses of nitrogen-containing bisphosphonates are typically 4 to 12 times as high as those used to treat osteoporosis. Whether lower doses can be used effectively to control metastatic bone disease is a matter for further study. Osteonecrosis of the jaw has developed far less often among patients who have received oral bisphosphonates at the lower doses used for osteoporosis than among patients who received the higher doses used for metastatic cancer. Among several million patients who have received oral treatment for osteoporosis, < 50 cases of osteonecrosis of the jaw have been reported to date^ref. Moreover, with > 60,000 patient-years of exposure to nitrogen-containing bisphosphonates in clinical trials of treatment for osteoporosis (involving follow-up for as long as 10 years in some patients), osteonecrosis of the jaw was not reported among the adverse events. Unpublished post-marketing surveillance data are also consistent with the infrequent occurrence of osteonecrosis of the jaw among persons being treated for osteoporosis. On the one hand, given that not all reported cases have been confirmed to be osteonecrosis of the jaw, and on the other hand, that there may be underreporting, 1 in 100,000 patient-years is a reasonable estimate of the incidence of osteonecrosis of the jaw in patients receiving oral nitrogen-containing bisphosphonates for osteoporosis. < 5 cases of osteonecrosis of the jaw have been reported among patients with Paget's disease of bone that was being treated with nitrogen-containing bisphosphonates. Because the estimate of the incidence of osteonecrosis of the jaw is based on incomplete data, well-designed prospective cohort studies with rigorous case-ascertainment criteria as well as documentation of risk factors and risk modifiers are needed^ref. The FDA now requires a precaution regarding osteonecrosis of the jaw in package inserts for all nitrogen-containing bisphosphonates. If there is a relationship between bisphosphonates and osteonecrosis of the jaw, what might explain it? The jaw is often subject to spontaneous, local trauma as well as trauma caused by dental procedures. The mucosa of the mouth is very thin and may therefore permit unroofing of the alveolar bone immediately beneath it when trauma or infection occurs. As potent inhibitors of osteoclast activity, the nitrogen-containing bisphosphonates might retard skeletal repair processes associated with trauma to or infection of the oral mucosa that involves the underlying bone. Since the jawbones are in constant use and are characterized by active remodeling, bisphosphonates might accumulate there preferentially, resulting in concentrations that exceed those found elsewhere in the skeleton. Other potential mechanisms include the possible antiangiogenic effects of nitrogen-containing bisphosphonates and the effects of these agents on T-cell function. The fact that the majority of reported cases of osteonecrosis of the jaw are associated with the use of high-dose intravenous bisphosphonates for metastatic bone disease suggests that the dose, duration of treatment, and route of administration, as well as coexisting conditions, concomitant treatments (glucocorticoids or immunosuppressive agents), and dental health, could all be related to the incidence of this complication. The use of bisphosphonates for osteoporosis in doses that are much smaller than those used for metastatic bone disease is consistent with the current view that osteonecrosis of the jaw is much less common in this setting. In Paget's disease of bone, bisphosphonate therapy is even more limited and osteonecrosis of the jaw is truly rare. The possibility that the risk of osteonecrosis of the jaw may be increased with the duration of therapy has led some to emphasize the need for a "drug holiday" for patients who are being treated with bisphosphonates for osteoporosis — perhaps a 1-year period without bisphosphonate therapy after 5 or more years of treatment. Patients should be advised to see their dentists before beginning intravenous bisphosphonate therapy so that their dental hygiene can be optimized and any necessary procedures can be performed in advance. Patients who are to receive oral bisphosphonates should also follow a regular program of oral health maintenance. Routine dental hygiene is important; this point should be emphasized, given that some dentists are reluctant to provide even routine oral health care for patients who are taking bisphosphonates. Such reluctance, however, seems unwarranted. Although there is no reason to stop bisphosphonate treatment for patients who are about to receive routine dental care, there is a debate about whether treatment should be withheld temporarily when more invasive dental care, such as a surgical procedure, is needed. Given the long half-life (measured in years) of bisphosphonates in bone, whether temporary cessation of treatment with these agents would reduce associated risks is not known; this question warrants study. For patients who are receiving bisphosphonate therapy for cancer and who are to undergo a major dental procedure, it seems reasonable to continue therapy in order to maximize control of the underlying malignant disease. For patients who are being treated for osteoporosis, however, it is unclear whether bisphosphonate therapy should continue or should be stopped until healing after the dental procedure is complete. Opinions, but little data, can be advanced for both approaches. It is generally agreed that one should use caution in recommending elective, invasive dental work such as dental-implant surgery in patients who are receiving nitrogen-containing bisphosphonates. Patients should contact their dentists if tooth or jaw pain develops while they are receiving such therapy.
Pharmacodynamics : bisphosphonates accumulate in the mineralized bone matrix and are released during bone resorption. First-generation, nonnitrogen-containing bisphosphonates are metabolized by osteoclasts to nonhydrolyzable cytotoxic ATP analogues^{ref1, ref2, ref3, ref4}. For example, clodronate is metabolized to AppCC12p, which, at high concentrations, inhibits mitochondrial ATP/adenosine diphosphate (ADP) translocase, thereby causing loss of the mitochondrial membrane potential and direct induction of apoptosis^{ref1, ref2, ref3}. The high affinity of bisphosphonates for bone mineral and subsequent uptake by activated osteoclasts during bone resorption ensures that cytotoxic concentrations of these metabolites only accumulate within osteoclasts. However, they may also accumulate within tumor cells growing in the bone because tumor cells stimulate osteolysis. In contrast, nitrogen-containing bisphosphonates (N-BPs), which include pamidronate, alendronate, ibandronate, risedronate, and zoledronic acid, affect osteoclast activity and survival through a different mechanism. After internalization, these compounds inhibit a key enzyme, FPP synthase, in the biosynthetic mevalonate pathway^{ref1, ref2, ref3, ref4, ref5}. As a result, N-BPs interfere with a variety of cellular functions essential for the bone-resorbing activity and survival of osteoclasts^{ref1, ref2}. Several intermediates in this pathway, including farnesyl pyrophosphate and geranylgeranyl pyrophosphate, are required for the posttranslational modification (i.e., prenylation) of GTP-binding proteins such as Ras, Rho, and Rac^ref. These signaling molecules are involved in the regulation of cell proliferation, cell survival, and cytoskeletal organization^{ref1, ref2, ref3, ref4}. In particular, inhibition of protein prenylation and Ras signaling within osteoclasts leads to defects in intracellular vesicle transport^ref. As a result, osteoclasts cannot form a tight-sealing zone or ruffled borders, which are required for bone resorption. Schematic representation of the mevalonate pathway and the effects of nitrogen-containing bisphosphonates^ref :

Recent studies have shown that N-BPs may have yet another mechanism of action. N-BPs also induce production of an intracellular ATP analogue known as Apppi^ref (triphosphoric acid 1-adenosin-5'-yl ester 3-[3-methylbut-3-enyl] ester), which may directly induce apoptosis similar to AppCC12p (i.e., a metabolite of clodronate) (Mönkkönen H, Lehenkari PP, Kellinsalmi M et al. A new mechanism of action for bisphosphonates: apppi dedicated cytotoxicity of N-BPs. Bone 2004;34:S66–S67). Inhibition of FPP synthase results in accumulation of isopentenyl diphosphonate, which can be metabolized to Apppi. The ability of various bisphosphonates (at 0.1-µM concentrations) to inhibit recombinant human FPP synthase activity^ref correlates well with their ability to induce production of Apppi in J774 cells. In this assay, clodronate serves as a negative control with little or no effect on FPP synthase activity, and it induces no Apppi production. Of the N-BPs tested, zoledronic acid demonstrated the highest potency in terms of both inhibition of FPP synthase activity^ref and production of Apppi (Mönkkönen H, Lehenkari PP, Kellinsalmi M et al. A new mechanism of action for bisphosphonates: apppi dedicated cytotoxicity of N-BPs. Bone 2004;34:S66–S67). The implication of this work is that N-BPs, by inhibiting FPP synthase, can potentially induce apoptosis of osteoclasts and tumor cells by at least 2 distinct pathways. It has been demonstrated that the potency of various N-BPs with respect to inhibition of FPP synthase activity also correlates well with their observed potency in terms of inhibiting bone resorption in vitro^{ref1, ref2}. Among the N-BPs tested, zoledronic acid was the most potent inhibitor of FPP synthase activity, followed by risedronate and ibandronate. The relative potencies of these 3 N-BPs in the FPP synthase assay correlate closely with their relative potencies in terms of inhibiting vitamin D₃-induced calcium release from mouse calvaria cultures^ref. These data suggest that inhibition of FPP synthase is a central mechanism by which N-BPs inhibit osteoclast-mediated bone resorption. Moreover, osteoclasts isolated from animals treated with N-BPs show a profound suppression of FPP synthase activity^ref. Therefore, FPP synthase appears to be one of the key molecular targets of N-BPs. Inhibition of protein prenylation in cancer cells is also thought to be responsible for many of the observed antitumor effects of N-BPs. Relative potencies of bisphosphonates with respect to inhibition of FPP synthase and bone resorption activity :
Evidence of antitumor effects :

bisphosphonate	FPP synthase IC50 (µM) (mean values calculated from dose-response plots of inhibition of FPP synthase in J774 cell homogenates based on 3 experimentsref)	bone resorption IC50 (µM) (inhibition of 1,25-dihydroxyvitamin D3-induced calcium release from mouse calvaria in vitro. Data represent means of several experimentsref)
zoledronic acid	0.02	0.002
risedronate	0.10	0.01
ibandronate	0.31	0.02
alendronate	0.50	0.05
pamidronate	0.85	0.2

• in vitro studies : bisphosphonates have demonstrated direct antitumor activity against a variety of tumor cell lines at concentrations ranging from 5–2,000 µM^ref. Bisphosphonates cause dose- and time-dependent inhibition of proliferation and induce apoptosis of multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, lung cancer, and osteosarcoma cell lines in vitro^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8, ref9, ref10, ref11}. For example, in studies with the human MDA-MB-231 breast cancer cell line, clodronate, pamidronate, and zoledronic acid demonstrated dose-dependent effects on cell viability, with IC₅₀ values of 700, 40, and 15 µM, respectively^ref. This effect was not caused by calcium chelation and appeared to be specific to tumor cells. Similar results have been observed with other breast cancer cell lines. For instance, dose-dependent increases in the proportion of apoptotic cells have been observed when Hs 578T cells were incubated with zoledronic acid^ref. Studies with MCF-7 cells have further shown that the effects of zoledronic acid on tumor cell viability and apoptosis could be reversed by incubation with geranylgeraniol, indicating that inhibition of protein prenylation can induce tumor cell apoptosis^ref. In vitro studies with several different prostate cancer cell lines, including PC-3 and LNCaP 23.1, have shown that zoledronic acid inhibits proliferation, induces apoptosis, and causes cell-cycle arrest in a dose-dependent manner^{ref1, ref2}. These are just a few examples of the antitumor activity of bisphosphonates against a wide variety of human and murine tumor cell lines, and in every instance where several bisphosphonates have been tested, zoledronic acid has demonstrated the most potent activity. In vitro studies have also shown that combining N-BPs with a variety of standard anticancer agents results in additive or synergistic antitumor effects against a range of tumor cell lines^{ref1, ref2, ref3, ref4} (Neville-Webbe HL, Evans CA, Coleman RE et al. Zoledronic acid (ZOL) in combination with doxorubicin (DOX) has synergistic effects on apoptosis of breast cancer cells (BCCs) in vitro [abstract]. Presented at the IVth International Conference on Cancer-Induced Bone Diseases, December 7–9, 2003, San Antonio, TX; Ullén A, Lennartsson L, Hjelm-Eriksson M et al. Additive/synergistic anti-tumoral effects on prostate cancer cells in vitro following treatment with a combination of docetaxel and zoledronate [poster]. Presented at the European Winter Oncology Conference (EWOC-8), January 19–24, 2003, Flims, Switzerland; Ullén A, Lennartsson L, Hjelm-Eriksson M et al. Additive/synergistic anti-tumoral effect on prostate cancer cells in vitro following treatment with a combination of gemcitabine and zoledronic acid. Proc Am Soc Clin Oncol 2003;22:432; Vogt U, Wassmann K, Bosse U et al. Enhancement of breast tumor growth inhibition (BTGI) in vitro through combination of CMF, epirubicin/cyclophosphamide (EC), epirubicin/paclitaxel (ET) and epirubicin/docetaxel (EDoc) with ibandronate (IB) or zoledronic acid (ZOL). Proc Am Soc Clin Oncol 2003;22:55; Witters L, Crispino J, Javeed M et al. Inhibition of growth of a human prostate cancer cell line with the combination of zoledronic acid and a COX-2 inhibitor. Proc Am Soc Clin Oncol 2002;21:5b). Jagdev et al.^ref were the first to show that the combination of zoledronic acid^{ref1, ref2} (10 µM) + paclitaxel (2 nM) enhanced apoptosis of MCF-7 breast cancer cells 4-fold compared with either agent alone. Similar results were reported when ibandronate or zoledronic acid were combined with epirubicin + docetaxel (Schlotter CM, Vogt U, Bosse U et al. Enhancement of breast tumor growth inhibition (BTGI) in vitro through combination of CMF, epirubicin/cyclophosphamide (EC), and epirubicin/paclitaxel (ET) with ibandronate (IB) or zoledronic acid (ZOL). J Bone Miner Res 2001;16(suppl 1):S191). In cultures of primary breast cancer cells, the concentrations of epirubicin + docetaxel were gradually reduced to suboptimal levels by serial dilution until there was little or no inhibition of tumor cell growth with these 2 drugs alone. However, the addition of 15 µM ibandronate or zoledronic acid resulted in 35% and 70% inhibitions of tumor cell growth, respectively. Combinations of zoledronic acid with taxanes also have demonstrated synergistic antitumor activity against prostate cancer cell lines. The combination of zoledronic acid (12.5 or 25 µM) with suboptimal concentrations of docetaxel (0.1 ng/ml) demonstrated additive and dose-dependent cytotoxic effects on PC-3 prostate cancer cells at 72 hours (Ullén A, Lennartsson L, Hjelm-Eriksson M et al. Additive/synergistic anti-tumoral effects on prostate cancer cells in vitro following treatment with a combination of docetaxel and zoledronate [poster]. Presented at the European Winter Oncology Conference (EWOC-8), January 19–24, 2003, Flims, Switzerland). In addition, recent studies with DU-145 prostate cancer and MCF-18 breast cancer cell lines have demonstrated that the combination of zoledronic acid with the cyclooxygenase-2 inhibitor SC236 had additive inhibitory effects on tumor cell growth^ref (Witters L, Crispino J, Javeed M et al. Inhibition of growth of a human prostate cancer cell line with the combination of zoledronic acid and a COX-2 inhibitor. Proc Am Soc Clin Oncol 2002;21:5b). These and many other studies have shown that N-BPs can enhance the cytotoxic and cytostatic effects of standard anticancer agents used to treat a variety of solid tumors. Recently, zoledronic acid also has been shown to possess antileukemic activity against a Ph⁺ cell line, and the combination of zoledronic acid with imatinib mesylate demonstrated synergistic antileukemic activity^ref. These findings are intriguing given that Bcr-Abl stimulates the Ras signaling pathway. 2 recent studies with breast cancer cell lines have begun to shed light on the possible mechanisms underlying the observed synergy between N-BPs and anticancer agents. In the first of these studies, MCF-7 breast cancer cells were incubated with zoledronic acid (25 µM) and doxorubicin (0.05 µM), and the effects of different sequences and incubation periods were tested. The only combination that resulted in synergistic enhancement of apoptosis was doxorubicin for 24 hours followed by zoledronic acid for 1 hour, whereas zoledronic acid administered either before doxorubicin or together with doxorubicin did not increase apoptosis (Neville-Webbe HL, Evans CA, Coleman RE et al. Zoledronic acid (ZOL) in combination with doxorubicin (DOX) has synergistic effects on apoptosis of breast cancer cells (BCCs) in vitro [abstract]. Presented at the IVth International Conference on Cancer-Induced Bone Diseases, December 7–9, 2003, San Antonio, TX). This suggests that exposure to doxorubicin at a concentration that was not cytotoxic sensitized tumor cells to the cytotoxic effects of zoledronic acid. A similar but opposite effect of sequencing was also reported by the same group when zoledronic acid (25 µM) was combined with TRAIL at a concentration of 10 ng/ml. Among 5 combinations tested, the only combination that produced synergistic apoptotic effects was zoledronic acid for 48 hours followed by TRAIL for 24 hours. This combination yielded 14.7% apoptotic cells compared with 0.7% for zoledronic acid alone and 2.7% for TRAIL alone (p < 0.001). The intriguing results of these in vitro studies suggest a novel approach to enhance the synergy between N-BPs and chemotherapeutic agents in the clinical setting.
• animal models : these in vitro findings are supported by data from many animal models showing that the newer N-BPs can significantly reduce the number and size of osteolytic lesions in tumor-bearing mice, reduce skeletal tumor burden, induce tumor cell apoptosis in bone lesions, reduce serum levels of tumor markers, and prevent formation of bone metastases^{ref1, ref2, ref3, ref4, ref5, ref6} (Green J, Gschaidmeier H, Yoneda T et al. Zoledronic acid potently inhibits tumour-induced osteolysis in two models of breast cancer metastasis to bone. Ann Oncol 2000;11(suppl 4):14; Nobuyuki H, Hiraga T, Williams PJ et al. The bisphosphonate zoledronic acid inhibits metastases to bone and liver with suppression of osteopontin production in mouse mammary tumor. J Bone Miner Res 2001;16(suppl 1):S191). Some models have even shown effects on visceral tumors and an improvement in survival of tumor-bearing mice, but these findings have been less consistently observed. Animal studies have focused on models of multiple myeloma, breast cancer, and prostate cancer. Using radiographic, histologic, and histomorphometric techniques, these studies have shown that N-BPs can inhibit the formation or progression of bone metastases and/or reduce skeletal tumor burden. Bisphosphonates have been administered either at the time of tumor cell inoculation (i.e., prevention setting) or after bone metastases are established (i.e., treatment setting). Animal models demonstrating antitumor effects of zoledronic acid^ref :

study	tumor cells	bisphosphonate	dose and schedule
Yaccoby et al.ref	primary human myeloma cells	zoledronic acid	100 µg/kg/week s.c.
		pamidronate	1.3 mg/kg every 2 weeks s.c.
Croucher et al.ref	5T2 murine myeloma	zoledronic acid	120 µg/kg twice weekly s.c.
Green et al. (Green J, Gschaidmeier H, Yoneda T et al. Zoledronic acid potently inhibits tumour-induced osteolysis in two models of breast cancer metastasis to bone. Ann Oncol 2000;11(suppl 4):14)	MDA-MB-231 human breast cancer	zoledronic acid	0.2–5.0 µg/day s.c.
		ibandronate	1.0 µg/day s.c.
		alendronate	10 µg/day s.c.
Peyruchaud et al.ref	MDA-MB-231 human breast cancer	zoledronic acid	3 µg/day x 12 days s.c.
Hiraga et al.ref	4T1 murine mammary carcinoma	zoledronic acid +	250 µg/kg
		UFT	20 mg/kg/day
Hiraga et al.ref	MDA-MB-231 human breast cancer	ibandronate	4 µg/day s.c.
Nobuyuki et al. (Nobuyuki H, Hiraga T, Williams PJ et al. The bisphosphonate zoledronic acid inhibits metastases to bone and liver with suppression of osteopontin production in mouse mammary tumor. J Bone Miner Res 2001;16(suppl 1):S191)	4T1 murine mammary carcinoma	zoledronic acid	0.5 or 5 µg every 4 days i.v.
Corey et al.ref	PC-3 and LuCaP 23.1 prostate cancer	zoledronic acid	5 µg/mouse twice weekly s.c.

Several models of multiple myeloma have been established and have consistently shown reductions in tumor-induced osteolysis and skeletal tumor burden by N-BPs^{ref1, ref2, ref3}. For example, in the 5T2 model of murine myeloma, treatment with zoledronic acid (120 µg/kg s.c. twice weekly) after osteolytic lesions were established significantly reduced development of new osteolytic lesions, reduced the bone surface occupied by osteoclasts and inhibited tumor-induced osteolysis, and reduced skeletal tumor burden as evidenced by serum paraprotein levels^ref. Moreover, treatment with zoledronic acid at the first sign of circulating paraprotein significantly prolonged disease-free survival in those mice.
Numerous studies in breast cancer models have also been reported. Zoledronic acid was shown to inhibit progression of established bone metastases and development of new bone metastases in two models of breast cancer^ref (Green J, Gschaidmeier H, Yoneda T et al. Zoledronic acid potently inhibits tumour-induced osteolysis in two models of breast cancer metastasis to bone. Ann Oncol 2000;11(suppl 4):14). In nude mice injected with human MDA-MB-231 breast cancer cells and allowed to develop osteolytic lesions, mice treated with zoledronic acid (0.2, 1.0, or 5.0 µg/day s.c.) had significantly less radiographic bone lesion area, by >80%, than controls (Green J, Gschaidmeier H, Yoneda T et al. Zoledronic acid potently inhibits tumour-induced osteolysis in 2 models of breast cancer metastasis to bone. Ann Oncol 2000;11(suppl 4):14). Ibandronate (1.0 µg/day) and alendronate (10 µg/day) resulted in nonsignificant reductions in bone lesion area (65% and 55% reductions, respectively). These findings were confirmed in another independent study using highly sensitive in vivo imaging of MDA-MB-231 cells genetically engineered to express green fluorescent protein^ref. Similar studies have been conducted with ibandronate in nude mice bearing MDA-MB-231 breast cancer cells, which typically form both adrenal and bone metastases. Treatment with ibandronate (4 µg/day s.c.) inhibited the radiographic progression of established osteolytic lesions and decreased skeletal tumor burden compared with controls^ref. However, administration of ibandronate at the time of tumor cell inoculation resulted in a twofold increase in adrenal tumor load^ref. In a murine breast cancer model, treatment with zoledronic acid (5 µg/day) for 7 days after injection of 4T1 murine mammary tumor cells (i.e., prevention setting) markedly decreased the formation of new bone metastases at day 28 (Green J, Gschaidmeier H, Yoneda T et al. Zoledronic acid potently inhibits tumour-induced osteolysis in two models of breast cancer metastasis to bone. Ann Oncol 2000;11(suppl 4):14). The observed decrease in radiographic bone lesion area was accompanied by an increase in the number of apoptotic osteoclasts and apoptotic tumor cells in bone lesions. Notably, the 4T1 mammary tumor model has provided the first in vivo evidence of synergy between zoledronic acid and chemotherapy. In animals with established orthotopic tumors, the combination of zoledronic acid (250 µg/kg) with 20 mg/kg/day of oral UFT (a combination of uracil and tegafur [4:1 molar ratio]) reduced skeletal tumor burden more effectively than either agent alone^ref. Similarly, the combination of ibandronate with doxorubicin (150 µg/day) has been investigated in the MDA-MB-231 model and was shown to have additive antitumor effects in bone^ref. Studies in a prostate cancer model have also recently been reported. In those studies PC-3 and LuCaP 23.1 cells were injected directly into the tibia of mice^ref; PC-3 cells form osteolytic lesions, and LuCaP 23.1 cells form osteoblastic lesions. The treatment group received zoledronic acid (5 µg s.c. twice weekly) either at the time of tumor cell injection or after tibial tumors were established (7 days for PC-3 tumors and 33 days for LuCaP 23.1 tumors). Treatment with zoledronic acid significantly inhibited growth of both osteolytic and osteoblastic metastases by radiographic analysis^ref and also reduced skeletal tumor burden as evidenced by a significant decrease in serum levels of prostate-specific antigen in animals bearing LuCaP 23.1 tumors^ref. The observed reduction in serum prostate-specific antigen levels provides compelling direct evidence of the antitumor activity of zoledronic acid in this animal model. The potential of zoledronic acid to prevent bone metastasis was also demonstrated in an animal model of prostate cancer^ref. In that model, mice were injected with PC-3 cells, and the incidence of bone metastases was studied in normal mice and in mice that were rendered androgen deficient by surgical castration. Androgen-deficient mice developed significantly more bone metastases than did intact control mice. This strongly suggests that excess bone resorption caused by androgen ablation can stimulate metastasis of PC-3 cells to the bone. This is consistent with current hypotheses of tumor cell metastasis to bone. Moreover, daily treatment with zoledronic acid significantly reduced the incidence of bone metastases in both normal and castrated mice. Although the majority of animal models suggest that the primary antitumor effect of bisphosphonates is manifested in the bone, where they reach the highest concentrations, preliminary data from the 4T1 mammary tumor model have demonstrated that zoledronic acid can also inhibit visceral metastases (Nobuyuki H, Hiraga T, Williams PJ et al. The bisphosphonate zoledronic acid inhibits metastases to bone and liver with suppression of osteopontin production in mouse mammary tumor. J Bone Miner Res 2001;16(suppl 1):S191). 4T1 cells expressing luciferase were used to quantitate tumor burden in mice. After tumor cell inoculation, mice were treated with zoledronic acid (5.0 µg every 4 days), which resulted in lower tumor burdens than in controls not only in bone but also in the liver and lungs^ref (Nobuyuki H, Hiraga T, Williams PJ et al. The bisphosphonate zoledronic acid inhibits metastases to bone and liver with suppression of osteopontin production in mouse mammary tumor. J Bone Miner Res 2001;16(suppl 1):S191). Treatment with zoledronic acid also prolonged survival of tumor-bearing mice. In the same model, ibandronate (4 µg/day s.c.) had no effect on lung or liver metastases or on survival^{ref1, ref2}. As mentioned above, treatment of mice bearing 5T2 myeloma cells with zoledronic acid (120 µg/kg s.c. twice weekly) also resulted in a significantly longer disease-free survival time (median, 47 days versus 35 days for untreated controls; p < 0.01)^ref. These animal models provide convincing evidence of the potential of bisphosphonates, particularly the more potent N-BPs, to reduce tumor burden in bone and inhibit formation and progression of bone metastases in a variety of tumor models. It is less clear whether bisphosphonates have antitumor activity beyond the bone, but it appears that zoledronic acid may be sufficiently potent to inhibit extraskeletal tumor cell growth and to prolong survival in some animal models.
Mechanisms of antitumor effects : the precise mechanisms responsible for the antitumor effects of bisphosphonates are beginning to be elucidated. Bisphosphonates appear to make the bone a less favorable site for tumor cell growth via the inhibition of osteoclast-mediated bone resorption and osteoclastogenesis, thereby reducing the release of growth factors that stimulate tumor growth in bone. In addition, bisphosphonates directly inhibit tumor cell growth and survival and the ability of tumor cells to colonize the bone. Either or both of these mechanisms may be at work.
• apoptosis : one of the primary mechanisms responsible for the direct antitumor activity of bisphosphonates is induction of tumor cell apoptosis. Both N-BPs and non-N-BPs appear to induce apoptosis of osteoclasts and tumor cells by activation of caspases^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8}. One mechanism by which bisphosphonates induce apoptosis is through production of ATP analogues (either as direct metabolites or as a result of inhibition of the mevalonate pathway), which can disrupt mitochondrial ATP/ADP translocase. A recent study investigating the mechanism by which zoledronic acid induced apoptosis in human breast cancer cell lines (MDA-MB-231 and MCF-7) indicated that this response was associated with cytochrome c release from the mitochondria and subsequent caspase-3 activation. It appears that N-BPs may induce cytochrome c release by modulating expression of Bcl-2, a key antiapoptotic regulatory protein. These events may be precipitated by inhibition of Ras activation, which requires protein prenylation (specifically farnesylation)^ref
• inhibition of tumor cell adhesion and invasion of the extracellular bone matrix : bisphosphonates have also been shown to inhibit adhesion of tumor cells to extracellular matrix (ECM) proteins and to inhibit the process of tumor cell invasion and metastasis^{ref1, ref2, ref3, ref4}. Using an in vitro Matrigel^TM-based invasion assay, bisphosphonates inhibit the ability of human breast and prostate cancer cells to invade the ECM^ref. In this assay, zoledronic acid and ibandronate caused dose-dependent inhibition of cell invasion through the Matrigel^TM at extremely low concentrations (10^–10 M) that did not inhibit tumor cell motility or induce significant apoptosis. Clodronate was approximately 6 orders of magnitude less potent in the same assay. Furthermore, the combination of ibandronate with taxanes enhanced the inhibitory effect on MDA-MB-231 cell invasion^ref. One contributory mechanism may be the inhibition of matrix metalloproteinase (MMP) activity, which is necessary for tumor cell invasion of the ECM^{ref1, ref2, ref3}. Bisphosphonates have been shown to inhibit the activity of MMPs produced by tumor cell lines, and this seems to correlate with reduced invasiveness in the Matrigel^TM assay^{ref1, ref2}. For example, zoledronic acid was shown to inhibit the production of MMP-2 and MMP-9 by PC-3 cells^ref. These data suggest a potential mechanism by which N-BPs may inhibit tumor cell invasion of the bone but cannot explain the apparent dependence of this effect on protein prenylation.Recent studies suggest that inhibition of tumor cell adhesion to ECM proteins and invasion through Matrigel^TM is dependent on inhibition of protein prenylation. In one study, zoledronic acid was shown to dose-dependently inhibit adhesion of MCF-7 and MDA-MB-231 cells to a variety of matrix proteins and this inhibitory effect was overcome by addition of either farnesol or geranylgeraniol or by the addition of a broad spectrum caspase inhibitor (Pickering LM, Mansi JL, Colston KW. Adhesion of breast cancer cells to extracellular matrices is inhibited by zoledronic acid and enhanced by aberrant Ras signalling. Proc Am Soc Clin Oncol 2003;22:863). Similar findings have been reported for alendronate. The inhibitory effect of alendronate on tumor cell invasion through Matrigel^TM was reversed by the addition of geranylgeraniol and trans-trans-farnesol^ref. Therefore, inhibition of the mevalonate pathway and induction of caspase activity are important for the inhibitory effects of N-BPs on tumor cell adhesion to the ECM and on invasiveness. Further, it has been shown that an activating Ras mutation enhances adhesion of a normal breast epithelial cell line to ECM proteins, suggesting that increased Ras activation in response to growth factor receptor signaling may increase the metastatic potential of breast cancer cells (Pickering LM, Mansi JL, Colston KW. Adhesion of breast cancer cells to extracellular matrices is inhibited by zoledronic acid and enhanced by aberrant Ras signalling. Proc Am Soc Clin Oncol 2003;22:863). Thus, by inhibiting protein prenylation and Ras signaling, zoledronic acid should reduce the metastatic potential of tumor cells.

% adherent cells versus controls when MDA-MB-231 human breast cancer cells were incubated with zoledronic acid for 24 hours (0.1 or 100 µM) before culture on plates coated with various extracellular matrix proteins. Adapted with permission from Pickering et al.
• antiangiogenic effects : in vitro and in vivo studies have further demonstrated that zoledronic acid has antiangiogenic effects. In vitro assays with human umbilical vein endothelial cells (HUVECs) have shown that zoledronic acid dose-dependently inhibited the proliferation of HUVECs induced by fetal calf serum and FGF-2 / bFGF, and these findings have been confirmed in vivo^ref. Systemic administration of zoledronic acid to mice resulted in potent inhibition of angiogenesis induced by s.c. implants impregnated with bFGF, with a dose of 3 µg/kg producing ED₅₀^ref. It has also been reported that zoledronic acid can reduce bone-tumor-associated angiogenesis in the murine 5T2 myeloma model^ref. In another series of experiments, zoledronic acid, as well as ibandronate, risedronate, and clodronate, inhibited formation of capillary-like tubules by HUVECs in vitro^ref. In vivo, zoledronic acid and ibandronate, but not clodronate, decreased revascularization (as measured by vessel area) of the ventral prostate gland in castrated rats treated with testosterone^ref. The inhibitory effect of zoledronic acid on endothelial cell adhesion and migration appears to be mediated, at least in part, by modulation of integrins (e.g., a_vß₃ and a_vß₅) that are involved in angiogenesis^ref (Bonjean K, Bellahcene A, Locigno R et al. Zoledronate modulates endothelial cell surface receptors involved in angiogenesis. Proc Am Assoc Cancer Res 2001;42:106). Interestingly, a_vß₃ integrin is also required for osteoclasts to adhere tightly to the bone and form resorption lacunae during active bone resorption, and a_vß₃ expression confers on tumor cells a greater propensity to metastasize to bone^ref. In fact, a small molecule inhibitor of a_vß₃ was recently shown to effectively prevent metastasis of MDA-MB-435 breast cancer cells to bone^ref. Therefore, effects on a_vß₃ could have pleiotropic effects on bone resorption and tumor metastasis. In addition, it has recently been reported that zoledronic acid decreases the survival of HUVECs by sensitizing them to TNF-induced programmed cell death^ref. Zoledronic acid also appears to modulate serum levels of proangiogenic growth factors such as vascular endothelial growth factor and bFGF in cancer patients^ref. These studies suggest a variety of potential mechanisms to account for the observed antiangiogenic effects of bisphosphonates.
• SERMs
• bone-forming agents
• fluoride
• AR agonists
• dual-acting bone agents (DABA)
• strontium ranelate (Osseor^®, Protelos^®; source : Fujisawa/Servier) inhibits preosteoclast differentiation and enhances preosteoblastic cell replication => increases collagen and noncollagen protein synthesis by mature osteoblast-enriched cells
• distal convoluted tubule diuretics
• Estrogens and progestins
• combination contraceptives : a compound, usually hormonal, taken orally in order to block ovulation and prevent the occurrence of pregnancy
• females contraceptives
• p.o. or i.m. PR agonists : levonorgestrel (LNG) 30 mg/day has variable effectiveness (faults in 0.5-2% within 12 months) and causes spotting, oligomenorrhea or rarely protracted amenorrhea. Most effective in puerperium, lactation (< 1% reaches milk) and after age 40 (when intrinsic fertility is already reduced), and epileptic patients (don't lower seizure threshold). Side efects : fatigue, decreased libido, depression
• p.o. ER agonists
• p.o. ER agonists + PR agonists : 21 pills per blister for a 3-wk course and a week of suspension to allow menstruation

Pharmacodynamics : inhibition of  hypothalamic and gonadotropic cells => anovulation and blockage at early follicular stage; tubal hypermotility, hyposecretion and hypovascularization => inhibition of sperm capacitation, reduced endometrial proliferation, earlier secretory stage and pseudodecidual stromal response => difficult nidation (intereceptive treatment); hyperviscosity of cervical mucus
Side effects : water retention (cellulitis, ocular hypertension), weight gain > 2 kg, spotting and metrorrhages in first months and with low EE pills, hypomenorrhea (< 50%; useful to prevent anemia and in adolescent's polymenorrhea and menometrorrhage; also decreased dysmenorrhea in some, while dysmenorrhea appears in others; also regression of ovarian cysts < 5 cm in diameter) due to reduced endometrial proliferation (progestin acting 3 instead of normal 2 weeks), decreased libido, dyspareunia (with low EE pills), photosensitivity (cloasma-like reactions, use high SPF filters)
• estrogens (from 50 down to 15 mg => reduction of thromboembolic risk) :
• increases HDL-Ch
• decreased LDL-Ch
• procoagulatory effect is decreased in low-dose pills, but thromboembolic risk still remains high in females with other risk factors (diathesis, smoking, hypertriglyceridemia, ...) and risk of postoperatory thrombosis is increased by 3-4 folds (OCs should be suspended 4 weeks before surgery; in urgent surgery, practice prophylaxis with low dose heparin); venous thrombembolism(not for transdermal ERT)  => pulmonary thromboembolism, ischemic stroke. Women using low-dose oral contraceptives are at an increased risk for a heart attack or stroke while taking the pill -- however the risk disappears after discontinuation. The findings could have further significance for those women taking low-dose oral contraceptives who already are at increased risk for such events because of polycystic ovary syndrome, or metabolic disorde. An insulin-sensitizing drug might confer better general health benefits than the oral contraceptive^ref
• systodiastolic systemic arterial hypertension (severe in 1-2%; contraindicated in patients with CRF)
• cholestasis and dyscholia (increased cholesterol content) =>
• cholelithiasis
• decreased risk of colorectal carcinoma
• reversible depression and psychosis (due to upregulation of hepatic tryptophan oxygenase => decreased serotonin pool in brain); worsening of autoimmune diseases (SLE, UC, CD); oncological risk :
• increased risk of hepatocellular adenoma but not carcinoma
• 20-50% decrease in ovarian cancer and endometrial carcinoma lasting 10-15 years after cessation
• increased risk of in situ cervical cancer and adenocarcinoma
• no increased risk of localized breast cancer : RR = 1.24 for current users, 1.15 after 1-4 yrs; 1.07 after 5-9 yrs; expecially when use began before age 20
• reduced short-term risk of developing multiple sclerosis by 40%. The pill could help delay onset of the debilitating neurodegenerative disease. Roughly 66% of multiple-sclerosis patients are female, and women generally have higher levels of oestrogen than men. So the disease has been blamed on the hormone in the past. In fact, some doctors warn women with a family history of multiple sclerosis not to take the pill. But recent evidence seems to suggest the opposite: mice given extra doses of oestrogen are protected against a neurological disorder similar to multiple sclerosis. Like the human illness, this disease involves destruction of nerve cells' fatty protective coating, called myelin. This layer normally enables these cells to transmit signals hundreds of times faster than their bare counterparts. The data came from the mid- to late-1990s, a time when UK doctors felt little hesitation in prescribing birth control to patients with a family history of multiple sclerosis, so such fears are unlikely be responsible for the relationship. But more research is necessary to establish a firm causative link. Long-term studies suggest oestrogen has no effect on a person's risk of developing multiple sclerosis : the protective boost from the hormone lasts only a few years: if a woman is going to get the disease, in the end she will. (Alonso, Archives of Neurology)
• reduce osteoporosis
• forestall heart disease
• relief from hot flushes
• first-generation progestins with residual androgenic activity increase LDL-Ch and decrease HDL-Ch more than EE; third generation progestins have no androgenic acitivity and benefit lipoprotein profile (reduced dosage => decreased negative effects on lipoprotein metabolism due to residual androgenic activity)
• women who had taken the pill at some point in their lives for > 1 year are 8% less likely to suffer any form of cardiovascular disease, including conditions such as heart attacks and hypercholesterolemia. The benefits increase the longer that they took the pill and are independent of other factors in their lives, such as not smoking. These findings fit with a growing body of evidence that shows that oestrogen helps protect blood vessels and prevent the growth of artery clogging deposits, but seem to contradict those from the Women's Health Initiative itself, which showed that older women taking HRT (a similar cocktail of oestrogen and progestin) increase their risk of cardiovascular disease. Older women may already be on the road to heart problems when they start taking HRT. In younger, healthier women taking the pill, the hormones may exert some protection.
Contraindications (> 2 risk factors before age 35-40) :
• absolute
• anamnesis of venous thromboembolism
• hypertriglyceridemia > 500 mg/dL at fasting (risk of acute pancreatitis)
• unexplained metrorrhage
• severe liver disease
• estrogen-sensitive proliferative diseases
• tumors : uterine leiomyoma or fibromatosis, endometrial adenocarcinoma, endometrioid ovary carcinoma, breast carcinoma (expecially the 5 years following therapy in advanced stages; low relapse risk in stage I patients)
• endometriosis
• relative
• first 2 years after menarche
• gastrointestinal absorption is decreased by broad spectrum antibacterials (ampicillin, neomycin, cloramphenicol, tetracyclin) or CYP-inducing drugs (barbiturates, rifampicin, carbamazepin, phenothiazines, primidone, chlordiazepoxide, mepobramate, diazepines, phenactin, pyrazolone, phenylbutazone)
• cholelithiasis
• cholestatic jaundice < 3 month old; Rotor and Dubin-Johnson' syndromes (beneficial in Gilbert's syndrome)
• mild chronic liver disease
• PR⁺meningiomas
Still effective if an administration delays of < 12 hrs : still protecting 3 days after discontinuation
No negative effects on future fertility, except mild reduction in fecundity in the 3 months after discontinuation. Drug-related discontinuation rate < 5% after 1 year
Monophasic formulations :
• intermediate dosage : ethinyl estradiol 50 mg + levonorgestrel (LNG) 250 mg (Novogyn 21^®, Evanor D^®, Microgynon^®)
• low dosage
• ethinyl estradiol 35 mg + cyproterone acetate (CPA) 2 mg (antiandrogen useful in females with hyperandrogenism : effects after 6 months) (Diane^®)
• ethinyl estradiol 30 mg + levonorgestrel (LNG) 150 mg (Egogyn 30^®, Ovranet^®)
• ethinyl estradiol 30 mg + desogestrel 150 mg (Practil 21^®, Planum^®)
• ethinyl estradiol 30 mg + gestodene 75 mg (Minulet^®, Ginoden^®)
• very low dosage
• ethinyl estradiol 20 mg + desogestrel 150 mg (Mercilon^®, Securgin^®)
• ethinyl estradiol 20 mg + gestodene 75 mg (Fedra^®, Harmonet^®)
• ethinyl estradiol 30 mg + levonorgestrel (LNG) 100 mg (Loette^®)
Biphasic formulations : ethinyl estradiol40 mg (first 7 capsules) and 30 mg (last 15 capsules) + desogestrel 25 mg (first 7 capsules) and 125 mg (last 15 capsules) (Gracial^®, Dueva^®)
Triphasic formulations :
• ethinyl estradiol 35 mg + norethisterone 500 mg (first 7 capsules), 750 mg (second 7 capsules) and 1,000 mg (last 7 capsules) (Trinovum^®)
• ethinyl estradiol 30 mg (first 6 capsules), 40 mg (second 5 capsules) and 30 mg (last 10 capsules) + levonorgestrel (LNG) 50 mg (first 7 capsules), 75 mg (second 7 capsules) and 125 mg (last 7 capsules) (Trinordiol^®, Trigynon^®)
• ethinyl estradiol 30 mg (first 6 capsules), 40 mg (second 5 capsules) and 30 mg (last 10 capsules) + gestodene 50 mg (first 7 capsules), 70 mg (second 7 capsules) and 100 mg (last 7 capsules) (Triminulet^®, Milvane^®)
Other formulations :
• ethinyl estradiol + norgestimate (Ortho Tri-Cyclen^®)
• ethinyl estradiol + drospirenone (Yasmin^®)
post-coital pill / after-sex pill / morning-after pill / day-after pill / emergency contraceptive pill (ECP) need to be taken within 72 hours since coitus : interception > contraception;
• high-dose ER agonists :
• ethinyl estradiol 5 mg/day for 5 days (equivalent to a 3-yr use of low-dose contraceptive !). Severe side effects
• ER agonists (from 50 down to 15 mg => reduction of thromboembolic risk) + PR agonists :
• ethinyl estradiol 100 mg + levonorgestrel (LNG) 500 mg within 72 hours in 2 administrations separated by 12 hrs
• Yuzpe method : a regimen for postcoital contraception, consisting of a combination of 200 mg ethinyl estradiol and 2 mg norgestrel in 2 divided doses 12 hours apart.
• PR antagonists :
• levonorgestrel (LNG) / SOH-075 (NorLevo^®) 1.5 mg given orally within 72 h of sexual intercourse. Levonorgestrel acts by interfering with ovulation. However, inhibition of ovulation occurs in only 50% of menstrual cycles and is most likely to occur when emergency contraception is given early in the cycle, at a time when risk of conception is low, and least likely to occur when given just before ovulation, when the probability of conception peaks. Moreover, the effi cacy of levonorgestrel declines with time after sexual intercourse, and there is only limited evidence that the drug is eff ective beyond 72 h after sexual intercourse. Emergency insertion of a copper intrauterine device is eff ective after 72 h;17 however, use is restricted by its availability and the need for insertion by a skilled health-care professional
• ulipristal acetate 30 mg is a selective progesterone-receptor modulator that seems to be as eff ective as levonorgestrel for prevention of pregnancy when used within 5 days (120 h) of unprotected sexual intercourse.
• mifepristone / RU486 600 mg
Side effects : nausea (50%), vomiting (20%), headache, mastodynia, polymenorrhea, metrorrhage, thromboembolism, no theratogenicity
• leptin receptor antagonists
They prevent ovulation but do not slow the rate of activation, so eggs are gradually lost. A drug that could delay follicular activation could be a useful contraceptive, keeping the eggs in storage until a woman decided the time had come to have a baby.
Routes of administrations (ROAs) :
• oral contraceptives (OCs)
• contraceptive skin patch (improved user compliance)
• contraceptive vaginal ring (increased bioavailability)
• male contraceptives
• PR agonists + AR agonists
• gossypol acetic acid
Varieties : oral contraceptives
• abortifacients / abortients : an agent which causes artificial abortion
• EP agonists
• methotrexate
• anti-preterm delivery
• tocolysis : inhibition of uterine contractions
• b₂-AR agonists (ritodrine, salbutamol and terbutaline)
• COX inhibitors : indomethacin, ketorolac. Fetal side effects : patent ductus arteriosus (PDA) and impaired renal function
• FP antagonists
• CCB : nifedipine
• OT antagonists : atosiban
• PR agonists
• inducers of fetal pulmonary maturation : a single course of antenatal steroids (ANS) increase expression of SP-B^ref
• i.m. betamethasone (most used in Europe) 2 times a day, the last at least 24 hours before fetal expulsion^ref. Contraindications : maternal bacterial infection, tuberculosis or peptic ulcer
• i.m. dexamethasone (most used in USA)

Side effects : increased gastroesophageal reflux (GERD)^ref, impairment in brain growth, principally affecting cerebral cortical gray matter, when used for more cycles at each threatened abortion^ref
Postnatal steroids should be avoided if at all possible. They might be indicated in very low doses for ventilator-dependent infants who might otherwise die without them^ref.
• post-menopausal HRT / menopausal hormone therapy (MHT) is used to prevent early menopause and treat postmenopause symptoms (not recommended after age 55)
• estrogen-only replacement therapy (ERT) : estrogens or ER agonists
• dienestrol cream : a mixture of dienestrol in a suitable water-miscible base; used topically for its estrogenic effect in the treatment of postmenopausal and senile vulvovaginitis, atrophic vaginitis, pruritus vulvae due to atrophic changes in the vulval epithelium, dyspareunia associated with atrophic vaginal epithelium, and prior to plastic pelvic surgery in menopausal cases.
Indications : hysterectomized females
Contraindications : functional uterus
Routes of administrations (ROAs) :
• oral route (high liver-mediated dyscrasia)
• transdermal route (low liver-mediated dyscrasia)
• vaginal route (when oral route is contraindicated, before and after lower genital tract surgery)
Side effects (see above) : 50% increased the risk to develop allergic bronchial asthma. HRT is classified as a Group 1 carcinogen by the IARC based on both animal and human data (IARC. Hormonal contraception and post-menopausal hormone therapy., IARC Lyon, France 1999). Estrogen is also known to have immunomodulatory effects^ref , and NHL is a tumor the development of which is sensitive to immunological function^ref. Animal studies have clearly shown that estrogen administration induces endometrial carcinoma, breast carcinoma (RR = 1.5), and ovarian cancers, and there are data showing that s.c. estrogen can also induce lymphoma^ref. In humans, HRT is associated with a substantially increased risk of endometrial carcinoma (when estrogen is unopposed by progestins) and a moderately elevated risk of breast cancer^ref. HRT also appears to be associated with a reduced risk of colorectal carcinoma, whereas data for ovarian cancers, liver, and thyroid cancer as well as cutaneous melanoma are equivocal or show no association^ref. There are few data regarding HRT and NHL. A case-control study reported a positive association of estrogen replacement therapy and NHL^ref, whereas another case-control study of intermediate and high grade NHL found a weak inverse association that was not statistically significant^ref. The early results (7-year follow-up) from the Iowa Women’s Health Study cohort found no association with HRT use^ref
• combined hormone replacement therapy (CHRT) : ER agonists + progesterone or PR agonists for > 12 days per cycle

Indications : functional uterus
Schedules :
• cyclic scheme : regular menstruation-like bleedings
• cyclic sequential scheme : estrogens since day 1 to 21, progestins for 12-14 days => , increased prevalence of irregular bleedings, lesser global dose. Side effect : premenstrual syndrome (PMS)
• cyclic combined scheme : association since day 1 to 21 => as for contraception, lesser global dose
• continue scheme : amenorrhea (differential diagnosis if uterine bleeding persists further month 6)
• continue sequential scheme : estrogens since day 1 to 28, progestins for 12-14 days => optimal endometrial protection
• continue combined scheme : association since day 1 to 28 => endometrial protection, amenorrhea, postmenopause
Routes of administrations (ROAs) :
• oral route (biodisponibility of natural progesterone < 10%; use synthetic progestins)
• intramuscular route (side effects : pain, hematoma or allergic inflammatory reactions at injection site)
• vaginal route (skips liver first-pass effet => plasma level = 12-13 ng/mL (as in luteal stage) for 12 hrs)
Side effects :
• decreased beneficial effects of estrogens on lipoprotein profile due to residual androgenetic activity
• RR = 2 for ..
• allergic bronchial asthma
• breast carcinoma : a woman aged 50 who does not take HRT has a risk of 6.1% of developing breast cancer over the next 30 years. A 50-year-old woman who has taken combined HRT, the treatment most commonly prescribed, has her risk increased to 6.7%. However, if a woman takes HRT for 10 years her risk rises to 7.7%^ref.
• RR = 2 for venous thrombosis
• aged 60-69 : 4.3 times higher risk
• aged > 70 : 7.5 times higher risk
• overweight women : 3.8 times higher risk
• obese women : 5.6 times higher risk
Over a 10-year period, CHRT causes an extra 18 cases of blood clots (venous thrombosis) per 1000 women
• no effect on systemic arterial pressure
Women who took soy protein (containing plant hormones including isoflavones, which it is claimed can provide the benefits of oestrogen without side effects) daily for a year gained no more benefits in memory and concentration, bone mineral density and cholesterol levels than those taking a placebo.
Despite one of the purported benefits of MHT was to improve the symptoms of urinary incontinence (UI), and it has often been prescribed to treat UI, data from the Women's Health Initiative (WHI) showed that MHT increased the incidence of all types of UI at 1 year among women who were continent at baseline. The risk was highest for stress UI (1.87-fold increased risk with CEE + MPA; CEE alone, 2.15-fold increased risk), followed by mixed UI (1.49-fold increased risk with CEE + MPA; CEE alone, 1.79-fold increased risk). The combination of CEE + MPA had no significant effect on developing urge UI, but CEE alone increased the risk by 1.32 fold. Among women who reported having UI at baseline, both frequency and amount of UI worsened in both trials. Women receiving menopausal hormone therapy were more likely to report that UI limited their daily activities and bothered or disturbed them at 1 year.
• Androgens
• AR agonists and antagonists
• 5a-reductase inhibitors

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