Female Gonadal Hormones and Drugs Winter 2024 Final PDF

Therapeutically Useful Estrogens & Progestins CLASS NAME 1. Natural Estrogens Estradiol 2. Conjugated Estrogens Estrogenic Compounds 3. Synthetic Estradiol Derivatives 4. Nonsteroidal Estrogens 5. Raloxifene (Evista®): Selective Estrogen Receptor Modulator (SERM) IMPORTANT NOTES Esters of estradiol...

Therapeutically Useful Estrogens & Progestins CLASS NAME 1. Natural Estrogens Estradiol 2. Conjugated Estrogens Estrogenic Compounds 3. Synthetic Estradiol Derivatives 4. Nonsteroidal Estrogens 5. Raloxifene (Evista®): Selective Estrogen Receptor Modulator (SERM) IMPORTANT NOTES Esters of estradiol can be administered IM High 1st pass metabolism with po administration Micronized estradiol (Estrace®) is oral and displays high absorption from GI tract Conjugated estrogenic steroids isolated from urine of pregnant mare (sulfate conjugates of estrone) Most common use: Hormone Replacement Therapy Premarin® Has ethinyl group (C=C) at C-17 which delays hepatic metabolism Major use = estrogen component of contraceptive agents Examples: Ethinyl estradiol (used in most combo contraceptives), mestranol, quinestrol Synthetic; oral administration Estrogen receptor agonists Examples: diethylstilbestrol (DES) – ↑ incidence of vaginal & cervical cancer in daughters of women who used it during pregnancy; Chlortrianesene = (TACE), Methallenestril Synthetic, nonsteroidal estrogen SERMs are agents with tissue-selective actions Raloxifene (Evista®) is a SERM – acts as a partial agonist of estrogen receptors in the bone Does not have a proliferative effect on the endometrium Has an anti-proliferative effect on estrogen receptor-positive breast cell cancer lines (antagonist) Does not alleviate the vasomotor symptoms associated with menopause Used to prevent and treat osteoporosis in postmenopausal women Less risk of breast/endometrial cancer Reduces total cholesterol and LDL, but does not increase HDL Adverse effects include hot flashes and leg cramps and a 3-fold increase in deep vein thrombosis and pulmonary embolism Bazedoxifene is a SERM with a tissue activity profile very similar to raloxifene. It is marketed as a fixed-dose combination with conjugated estrogen s (Duavee®) to prevent postmenopausal osteoporosis Gonadotropins FSH -like Gonadotropins LH-like Human chorionic gonadotropin (hCG) Choriogonadotropin alfa = (r-hCG) Ovidrel® Urinary hCG (Pregnyl®, Follutein®) others Recombinant LH (rLH) (Luveris®) Raloxifene and Duavee® prevent bone loss, improve bone mineral density (BMD) and decrease the risk of vertebral fracture Bazedoxifene/conjugated estrogens is also approved for treatment of menopausal vasomotor symptoms. The bazedoxifene component prevents estrogen-induced endometrial hyperplasia so that co-administration of a progestin is not necessary hMG (“menotropins”): Extracted from the urine of postmenopausal women, it consists of partially catabolized FSH and LH. The agent is primarily used s.c for its FSH-like properties in fertility protocols although potency is 4% that of FSH. Recombinant gonadotropins have to a large degree replaced hMG (and uFSH) in fertility protocols uFSH (“urofollitropin”) a purified preparation of human FSH that contains virtually no LH → obtained and purified from the urine of postmenopausal women Given by subcutaneous injection, it is used in combination with human chorionic gonadotropin (hCG) to assist in ovulation and fertility. Urofollitropin is also used to help the ovaries produce multiple eggs for use in "in-vitro" fertilization. rFSH (“follitropin alpha or recombinant FSH”): modified recombinant form of FSH used in fertility protocols → used in stimulating ovulation in women with hypothalamic or pituitary dysfunction; since ovulation also depends on a surge of LH, this and the above agents must be used in conjunction with an appropriately timed LH-like agent If the ovulated oocyte is fertilized and implants in the uterine wall, the choroid layer of the developing syncytiotrophoblast (primitive embryo/placenta) secretes hCG which sustains the corpus luteum for the 1st trimester of pregnancy, allowing it to continue to synthesize progesterone & estrogen. In turn, progesterone maintains the endometrial lining and the placenta to support pregnancy Recombinant/ or extracted urine of pregnant women Detected in the pregnancy test (basis of the test) Highly resembles LH →at one time there was no other form of LH commercially available (now there is a recombinant form of LH available: rLH = leutropin-alpha (Luveris®). hCG or rLH are administered at midcycle (after early-cycle tx with one of the FSH- like agents) to “trigger” ovulation in fertility protocols Conjugated Estrogens: What is an estrogen response element (ERE)? Estrogen is responsible for enhancing the synthesis of many different proteins, all of which are coded for on specific genes distributed amongst the chromosomes of the human genome. Before each gene there is a sequence of nucleotides that is known as the promoter region for that gene. It is this promoter region to which the activated estrogen receptor dimer binds to initiate the synthesis of the corresponding mRNA (transcription)for that gene. The stretch of nucleotides (promoter region of the gene) to which the dimeric estrogen receptor binds is known as an estrogen response element.(ERE) Since estrogen is responsible for enhancing the synthesis of many different kinds of proteins, there will likewise be many EREs found throughout the genome. Structures of Estradiol and currently-marketed Selective Estrogen Receptor Modulators (SERMS) Mechanism of Action of a Selective Estrogen Receptor Modulator (SERM) Each class of SERMs (orange symbols) has a slightly different shape, although all will bind to the estrogen receptor. When it binds to an estrogen, antiestrogen, or SERM, the estrogen receptor undergoes a conformational change that permits its spontaneous dimerization and facilitates the subsequent interaction of the dimer with estrogen response elements (EREs) located within target genes. The estrogen-receptor–ligand complex also leads to binding of various coregulator proteins that vary with its conformational structure. Some estrogen-receptor–SERM complexes favor corepressor recruitment (red) that, in a given target cell, increases its antagonist activity, and others favor coactivator recruitment (blue) that increases its agonist activity. Some SERMs may also facilitate the interaction of the estrogen receptor with yet-to-be-identified coactivators (green) with which estrogens or antiestrogens would not normally couple. It has now been determined that estrogen facilitates the interaction of the estrogen receptor with coactivators. The antagonist-activated estrogen receptor, on the other hand, interacts preferentially with corepressors. The binding of different SERMs to the receptor permits the receptor to adopt conformational states that are different from each other and also distinct from that induced by classic estrogen agonists or antagonists. The implication of this model is that SERM activity will be influenced by the relative levels of expression of the coregulator proteins (corepressors and coactivators) that are expressed in different target cells. Tissue-specific estrogenic and antiestrogenic activity of SERMs Liver Medication Breast Bone Lipids Coagulation SHBG Sex hormonebinding globulin Brain IGF-1 Insulinlike growth factor 1 Uterus Vagina Hot Gonadotropins flashes Estradiol + + + + + + + + + + "Ideal SERM" – + + ± ± ± – + + ± Bazedoxifene – + + + + ? – ± – ? Clomifene – + + ? + + – ? – ± Lasofoxifene – + + + ? ? ± ± – ? Ospemifene – + + + + + ± ± – ± Raloxifene – + + + + + ± – – ± Tamoxifen – + + + + + + – – ± Toremifene – + + + + + + – – ± Effect: + = Estrogenic / agonistic. ± = Mixed or neutral. – = Antiestrogenic / antagonistic. Note: SERMs generally increase gonadotropin levels in hypogonadal and eugonadal men as well as premenopausal women (antiestrogenic) but decrease gonadotropin levels in postmenopausal women (estrogenic). Structures of Progesterone and Testosterone Structures of Some C-19 Progestins Structures of Two Marketed C-21 Progestins Progesterone. Micronized Progesterone (Prometrium®) Progesterone & Progestins C-21 Synthetic Progestins C-19 Progestins (general characteristics): Progestins (cont’d) 1st generation C-19 Progestins with androgenic side effects → Competitive antagonist at aldosterone receptors → counteracts estrogen-induced aldosterone release Synthetic analogs of progesterone = ”progestins” Significant 1st pass metabolism Metabolites: anxiolytic, sedative, hypnotic properties Orally active – need to counteract large first-pass metabolism → higher percentage absorbed from GI tract due to faster dissolution and greater surface area. The resulting greater amount of absorption from the GI tract allows allows clinically-relevant serum concentrations to be attained despite the large first-pass metabolism (This is also true for micronized estrogen) More like progesterone – retain all 21 carbons Produce more physiological endometrium than C19s 17 α- acetoxy derivatives: Medroxyprogesterone acetate (Provera®), also available in a depot formulation (Depo-Provera®) for contraception that lasts 3 months Megestrol acetate (Megase®) – stimulates appetite in HIV patients with wasting Promote secretory functions of endometrium Can maintain endometrium & placenta Compete with aldosterone (antagonists) Little /no estrogenic or androgenic effects Remove 2 –carbon acetyl group on D ring → most replace acetyl group with hydroxyl (OH) group so they are actually testosterone derivatives Do not compete with aldosterone for its receptor Thinning of the endometrium (glandular atrophy) Do not support pregnancy! Effective gonadotropin inhibitors (used in O.C’.s) Some have androgenic and/or estrogenic effects Promote viscous secretion of mucous in the cervix to cause hostile environment for sperm migration (important action in contraception) Most of the 1st generation C-19’s (and the ones named in the next box) are actually nortestosterone derivatives and often (not always) contain “no-“ or “nor-“ in the name of the drug: e.g., norethindrone acetate, ethynodiol acetate, norgestrel, levonorgestrel, norethynodrel C-19 Progestins with minimal or no overall androgenic side effects C-19 Progestins with anti-androgenic activity Drospirenone (Yaz®, Yasmin®) Clomiphene citrate (Clomid®) Norgestimate, Desogestrel, Etonorgestrel, Norelgestromin, Segesterone, Gestodene May have some inherent androgenic activity but overall they demonstrate little or no androgenic activity because they increase the synthesis of sex hormone binding globulin (SHBG) which binds to (“ties up”) serum testosterone. This action decreases serum levels of “free” testosterone thereby hindering its activity. Net effect = ↓ androgenic effects (less acne/oily skin, weight gain) Used in combination with ethinyl estradiol for contraception Structural analogue of spironolactone: antagonizes the receptor for aldosterone (i.e., the ”mineralocorticoid receptor”) to prevent Na+ & water retention → can produce hyperkalemia Antagonist of androgen receptor → minimal acne, oily skin, hirsuitism, weight gain Adverse effects: Increased risk of hyperkalemia due to blockade of mineralocorticoid (aldosterone) receptor Higher incidence of thromboembolism compared to other oral contraceptives ?? An estrogen receptor antagonist that acts on the hypothalamus → occupies estrogen feedback receptor longer than estradiol normally does preventing recycling of the receptor. This action effectively “depletes” estrogen (feedback) receptors in hypothalamus thereby increasing the release of GnRH, which in turn increases the release of FSH and LH from the pituitary → increases chance of ovulation Used as fertility agent (10% are multiple births) If FSH levels don’t markedly increase, combine clomifene with hMG or rFSH (followed by a midcycle hCG “trigger”) to bring about ovulation Adverse effects = hot flashes (due to hypothalamic block); breast tenderness & heavy menses (due to too much estrogen later in cycle) Caution: Visual symptoms: blurred or double vision, floaters, light sensitivity, scotoma Combined w metformin to enhance fertility of women with polycystic ovary syndrome Dosing begins at or near the 3rd day of the menstrual cycle and is continued for five days Polycystic Ovary Syndrome (PCOS) Often associated with obesity and hyperinsulinemia due to insulin resistance as might be found in a Type 2 diabetic, or perhaps a chronic overeater of carbohydrates. Insulin (receptor) resistance leads to a compensatory increase in the release of insulin in the early stages of Type 2 diabetes. In reproductively normal women, insulin administration increases the LH pulse frequency, consistent with a stimulatory effect of insulin on GnRH pulsatility. This increased LH leads to overproduction of androgens in the thecal cells of the ovary → decreased follicular development, decreased SHBG production by the liver (increases unbound ( “free”) testosterone, increased testosterone synthesis. Combination oral contraceptives can reduce the dermatological manifestations (acne & hirsuitism) of hyperandrogenism in women with POCS. The relevant mechanisms of action include (1) inhibition of gonadotropin secretion and thereby ovarian androgen secretion; (2) an increase in the synthesis of SHBG which leads to a reduction in free androgen levels; and (3) inhibition of adrenal androgen secretion (mechanism unknown) Synthesis of Androgens, Estrogens, and Progesterone in the Thecal and Granulosa Cells of the Ovarian Follicle Note: CYP19 is more commonly referred to as “Aromatase” (i.e., CYP19 and aromatase are the same enzyme) The overall goals of therapy of women with PCOS include: Amelioration of hyperandrogenic features (hirsutism, acne, scalp hair loss) Management of underlying metabolic abnormalities and reduction of risk factors for type 2 diabetes and cardiovascular disease Prevention of endometrial hyperplasia and carcinoma, which may occur as a result of chronic anovulation Contraception for those not pursuing pregnancy, as women with oligomenorrhea ovulate intermittently and unwanted pregnancy may occur Ovulation induction for those pursuing pregnancy Note: High and low GnRH pulse frequencies favor LH and FSH release, respectively. However, the mechanisms through which pituitary gonadotropes “decode” pulse frequency remains elusive. Treatment of Endometriosis; Endometriosis is defined as ‘the presence of viable, estrogen sensitive, endometrial-like glands and stroma associated with inflammatory response outside the uterus’. Compared with normal endometrium, endometriotic implants are characterized by overproduction of prostaglandins and local production of estrogens and cytokines, which synergize the activities of each other, promote implantation of ectopic endometrium, and cause the pain associated with endometriosis. In addition, aromatase overactivity results in increased COX2 expression favoring prostaglandin E production, which, in turn, upregulates estrogen synthesis pathways. Interventions that reduce ovarian estrogen production reduce this synergistic process, thereby reducing or eliminating endometriosis-related pain Hormonal contraceptives. Birth control pills, patches and vaginal rings, decrease FSH and LH release from the pituitary to control the hormones (e.g., estrogen) responsible for the buildup of endometrial tissue each month. Many have lighter and shorter menstrual flow when they're using a hormonal contraceptive. Using hormonal contraceptives — especially continuous-cycle regimens — may reduce or eliminate pain in some cases Gonadotropin-releasing hormone (Gn-RH) AGONISTS dosed in a “continuous” fashion , or GnRH receptor ANTAGONISTS. These drugs block the production of ovarian -stimulating hormones, (FSH and LH) lowering estrogen levels and preventing menstruation. This causes endometrial tissue to shrink. Because these drugs create an artificial menopause, taking a low dose of estrogen or progestin along with Gn RH agonists and antagonists may decrease menopausal side effects, such as hot flashes, vaginal dryness and bone loss. Menstrual periods and the ability to get pregnant return when these agents are discontinued o In the USA, three GnRH agonists are approved by the FDA for treatment of pelvic pain caused by endometriosis: leuprolide, nafarelin, and goserelin. They are approved for six months of continuous use for this indication, but may be repeated or continued for an additional six months. This duration of therapy limitation(s) is due to concern about the significant bone loss that occurs with “ continuous” GnRH agonist therapy Progestin therapy. Progestin therapies, including an intrauterine device with levonorgestrel (Mirena, Skyla), contraceptive implant (Nexplanon), contraceptive injection (Depo-Provera) or progestin pill (Camila), can halt menstrual periods and the growth of endometrial implants, which may relieve endometriosis signs and symptoms. Progestins inhibit endometrial tissue growth by causing initial decidualization and then atrophy. Additional proposed mechanisms of action include suppression of matrix metalloproteinases, a class of enzymes important in the growth and implantation of ectopic endometrium Aromatase inhibitors. Aromatase inhibitors are a class of medicines that inhibit the synthesis of estrogen. A physician may recommend an aromatase inhibitor along with a progestin or combination hormonal contraceptive to treat endometriosis. Tamoxifen (Nolvadex®) Toremifene(Fareston®) Fulvestrant (Faslodex®) Therapeutic Agents That Act by Altering Hormone Control Mechanisms (cont’d) Anastrozole (Arimidex®) Letrozole (Femara®) Examestane (Aromasin®) GnRH (Gonadorelin) GnRH Analogs: Leuprolide Nafarelin Gosrelin Tamoxifen - a drug of choice for tx of breast cancer Think of Tamoxifen as a SERM which is an antagonist at estrogen receptors in the breast, but a partial agonist at estrogen receptors in the endometrium and bone Prevents bone loss and does not produce adverse effects on serum lipids Used for treatment of breast cancers that are estrogen receptor-positive S.E. = hot flashes and sweats, N/V, loss of sex drive, vaginal drying/itching Toremifene is similar to tamoxifen in most aspects Fulvestrant = pure estrogen receptor antagonist; used in tamoxifen-resistant patients Anastrozole & Letrozole = competitive, reversible inhibitors of aromatase (the enzyme that converts testosterone/androgens to estradiol or estrone Examestane = irreversible aromatase inhibitor All 3 used in treating breast cancer in pts resistant to tamoxifen Side effects: hot flashes & sweats, loss of sex drive, vaginal drying/itching, joint/muscle pain; increased risk of osteoporosis due to decrease in bone mineral density Peptides that are agonists at GnRH receptors (as observed when dosed intermittently) Intermittent (pulsatile) dosing = stimulate FSH / LH release (IV or SC) = replacement therapy: o Gonadorelin - used to treat infertility caused by hypothalamic hypogonadism (program pump to administer) o Side effects: headache, light-headedness nausea, flushing, local swelling at injection site (long-term use) generalized hypersensitivity, dermatitis ,and rarely acute hypersensitivity including bronchospasm and anaphylaxis Continuous dosing = inhibit FSH / LH release by downregulating GnRH receptors in the pituitary (use long-acting analogs or depot formulations). The down regulation process takes about 2 weeks to be established, therefore during the initial two weeks of treatment the pituitary will respond to these agents (since they are agonists at GnRH receptors) by increasing the release of FSH and LH which, in turn, will lead to increased synthesis of estrogen & progesterone in women, and increased testosterone synthesis in men. After 2 weeks of continuous treatment the GnRH receptor downregulates meaning FSH and LH will not be released by the pituitary and subsequently estrogen synthesis (women) and testosterone synthesis (men) will cease. This is the desired goal when dosing in a continuous fashion:. o Leuprolide, Gosrelin used to treat prostate cancer: ▪ In men = increase in serum testosterone levels for about 1-2 weeks: can precipitate pain in men with bone metastases or cause prostate gland “flare-up”. Initial growth of tumor can cause neurological symptoms. Can temporarily worsen urinary obstruction when treating prostate cancer. Other side effects in men include hot flashes & sweats (60%), edema (13%), gynecomastia, decreased libido, decreased hematocrit and muscle weakness ▪ In children leuprolide or nafrelin are agents of choice to treat central precocious puberty: well tolerated, but may see temporary exacerbation of precocious puberty during first weeks of therapy; injection site reactions (5%); nafarelin nasal spray may cause sinusitis. Uses in women ( leuprolide, goserelin, nafarelin): treatment of endometriosis, uterine fibroids, POCS, hirsutism, dysfunctional uterine bleeding, premenstrual syndrome o Also used in assisted reproduction ▪ In women: get hot flashes/sweats (90%), headache (30%), depression, diminished libido, general pain, vaginal dryness. Ovarian cysts may develop within first 2 months of therapy and generally resolve by 6 weeks of therapy. Osteoporosis with longterm use. Contraindicated in pregnancy and breast feeding GnRH Antagonists: Cetrorelix (Cetrotide®) Ganirelix (Orgalutran®, Antagon®) Degarelix (Firmagon®) Elagolix (Orilissa®) Bromocriptine mesylate (Parlodel®) (fertilization) regimens → suppress endogenous FSH/LH release and give exogenous FSH followed by midcycle LH to correct timing for fertilization o Useful in treating endometriosis since they inhibit FSH and LH release to prevent ovarian synthesis of estradiol Pure GnRH receptor antagonists MOA: bind to pituitary GnRH receptors to competitively inhibit FSH / LH release Used for in vitro fertilization (prevents LH surge & thus spontaneous premature ovulation which would preclude laproscopic harvest of the ova) Also used to treat endometriosis or uterine fibroids Degarelix is approved for treatment of advanced prostate cancer Side effects of GnRH antagonists hot flushes, headache, nausea and weight gain. When used in fertility treatment they can also be associated with abdominal pain and ovarian hyperstimulation. Selective D-2 dopamine receptor agonist (mimic effects of dopamine) → inhibits prolactin release from anterior pituitary Used for treatment of hyperprolactemia, infertility due to hyperprolactemia, and Parkinson’s disease Caution: increased risk of stroke in post-partum women who no longer wish to lactate Oral Contraceptives o Combination OC’s contain a mixture of an estrogen & progestin which act by inhibiting ovulation ▪ Estrogen is considered the major ovulation inhibitor Relatively high serum level of estrogen inhibits release of FSH / LH from pituitary (via negative feedback) so that the follicle does not develop ▪ MOA Progestins decrease the frequency of pulses of GnRH release from the hypothalamus. Because the proper frequency of LH pulses is essential for ovulation, this effect of progestins likely plays a significant role in the contraceptive action of these agents C-19s produce a thick secretion of mucus in the cervix, which is a hostile environment for sperm migration (major MOA in contraception) Desynchronization of the endometrial changes needed for implantation C-19s produce glandular atrophy of the endometrium Inclusion in combination OC’s ensures a “physiological” withdrawal bleeding that resembles normal menstruation when placebo pills are taken o As noted above, continual relatively high serum levels of estrogen & progestin in blood prevent GnRH, LH, & FSH release by negative feedback mechanisms – so ovulation does not occur o Changes in milieu of mucosal lining of cervix & uterine endometrium o Changes the motility & secretion pattern within fallopian tube Therapeutic regimens o Usually use 35mcg or less of ethinyl estradiol in combination OC’s Yaz® (ethinyl estradiol + drospirenone) is also used to treat the symptoms of premenstrual dysphoric disorder (PMDD), such as anxiety, depression, irritability, trouble concentrating, lack of energy, sleep or appetite changes, breast tenderness, joint or muscle pain, headache, and weight gain. It can be used to treat moderate acne in women > 14 years of age. Combined OC’s are often prescribed to women with a history of painful ovarian cysts to suppress ovulation and subsequent formation of new cysts. OC’s do not appear to aid regression of existing functional ovarian cysts. Contraception: Drug Options Combined Features: Daily low-dose progestin only tablets (“minipill”) “POP” Progestin Only Pill Phasic Continuous or extended-cycle regimens Depot Therapy Patch: Estrogen & progestin: many regimens consist of 21 daily “active” pills followed by 7daily placebo pills ( 21/7 regimen) Theoretical effectiveness = 99.9% Use effectiveness = 97-98% Yaz ® utilizes a 24/4 regimen Progestin only: Commonly uses norethindrone (0.35 mg) or drospirenone (3-4 mg); norethindrone dose is less than that in combination OC’s Less reliable as an inhibitor of ovulation (block in only 75-80% of cycles) than combined estrogen/progestin OC’s Increased incidence of unpredictable spotting & breakthrough bleeding, acne flair, increased prevalence of ovarian cysts Use effectiveness = 96-97.5% (less than combo therapy) Advantage = serious side effects of combo therapy (e.g., clotting, thrombosis) are due to estrogen component and are hence minimized Varying doses of estrogen & progestin components during the month to more closely approximate a normal menstrual cycle Continuous: Combination estrogen/progestin pill every day for 1 year; can stop all menstrual bleeding during this time frame Extended-cycle: Combination pill taken daily for 84 days, followed by a week of placebo pills (so-called “84/7” regimen). Menstrual bleeding occurs during the placebo week. Continuous or extended-cycle regimens have several potential benefits. They prevent hormone changes responsible for bleeding, cramping, headaches and other period-related discomforts. Injections of long-lasting progestins: Medroxyprogesteron acetate (Depo-Provera®) – give IM 1x / 3 months Apply patch once a week for three weeks then no patch for one week. Xulane® Subdermal Implants Nexplanon® Vaginal ring NuvaRing® Post-coital Contraceptives Intrauterine (IUD) Progestin: Mirena®, Skyla®, Liletta® Copper: Paragard® Mifepristone (RU486) Characteristic Patch contains ethinyl estradiol + norelgestromin Capsules of etonorgestrel under skin for slow release (work up to 3 years) Implant must be removed after three years Contains ethinyl estradiol + etonorgestrel. Inserted once a month and worn for three weeks. A new ring is inserted each month Annovera® = segesterone + ethinyl estradiol. It is inserted once a month for three weeks, but unlike NuvaRing, the ring is reusable for one year MOA: prevent implantation of the fertilized ovum and/or alter motility of the fertilized ovum through Fallopian tube Formerly used high doses of estrogens → severe nausea/vomiting Plan B® = L-norgestrel 0.75mg twice daily for 1 day (progestin only) T-shaped piece of plastic which releases the progestin, levonorgestrel Can be used as contraception if breast-feeding Also can use a copper IUD for contraception. Copper acts as a spermicide within the uterus. The presence of copper increases the levels of copper ions, prostaglandins, and white blood cells within the uterine fluid Progesterone antagonist that inhibits the actions of progesterone on the uterus during luteal phase: facilitates leutolysis, menstruation, uterine motility, detachment of the embryo from uterine wall leading to abortion → administered with misoprostol (a prostaglandin) to expel embryo Name Nausea, Mastalgia, Edema Depression (?) Migraine Headache Breakthrough Bleeding Side Effects of Oral Contraceptives Important Notes: Estrogen-induced May be relieved by lowering estrogen content Debated whether this is really OC use-related Certain progestins induce enzyme that destroys tryptophan (which is a serotonin precursor) decreased CNS serotonin → depression Estrogen-induced (due to estrogen component) More common with progestin-only OC’s (POPs) Does not require discontinuation of agent Combination OC’s: Bleeding early in cycle – b/c of too little estrogen Bleeding later in cycle – b/c of too little progestin Bleeding irregularities: Irregular menstrual bleeding patterns Androgenic Side Effects POPs: Norethindrone users have more frequent, longer episodes and shorter, less predictable intervals than combined pill users, but up to onehalf of users experience a mostly regular monthly bleeding pattern. Amenorrhea and prolonged episodes of bleeding also occur, but less frequently than in depot-medroxyprogesterone acetate (DMPA) users. More common with androgenic 1st generation progestins used in POPs Chloasma Infections: Biochemical Alterations Induced by OC’s Cholestatic Jaundice Gall Bladder Enhanced blood coagulation Increased levels of plasma proteins Alterations in carbohydrate metabolism Alterations in blood lipids Cardiovascular disorders: Venous thromboembolic disease Myocardial Infarction Cerebrovascular Disease Androgenic side are seldomly observed in combo OC users Ex: Hirsutism, acne, oily skin; weight gain? Estrogen-induced pigmentation of skin More common in women w/ darker complexions Ureteral dilation similar to that seen in pregnancy: Increased bacteruria, and vaginal infections that are harder to treat (related to mucosal alterations ??), but decreased incidence of pelvic inflammatory disease (PID) b/c thick mucosa resulting from progestin component prevents bacterial penetration into pelvic structures High doses of Estrogens, and C-19 and C-21 17α-acetoxy progestins have been associated with cholestatic jaundice, although rare Estrogen-induced → estrogens increase cholesterol secretion into bile, but decrease bile acid secretion leading to increased saturation of the bile with cholesterol; this is responsible for: gallstone formation & perhaps gall bladder disease (OC’s are contraindicated in pts with current gall bladder disease) Estrogen-induced – increased synthesis of several clotting factors OC’s also decrease antithrombin III Estrogen-induced: ↑ thyroid hormone-, cortisol-, & Vitamin D-binding globulins Progestins ↑ insulin release Long-term effect may be reversible reduction in glucose tolerance due to insulin resistance EE – favorable HDL/LDL profile; slight ↑ TG’s C-19 1st generation progestins – slight ↑LDL and ↓ HDL (believed to be clinically-insignificant) Newer progestins – no significant change in LDL or HDL profiles compared to non-users of OC’s Risk appears to be concentrated in women 35y/o or older & who are heavy smokers Estrogen-related OC use decreases serum antithrombin III levels Estrogens increase certain clotting factors Surprisingly, incidence does not appear to be related to age or smoking habits According to a 2018 systematic review, levonorgestrel was associated with the lowest risk of blood clots (venous thromboembolism) of any combined estrogen/progestin contraceptive Smokers are definitely at increased risk of MI Estrogens increase clotting factors Estrogen-related ?? Liver Disorders Cancer Ectopic Pregnancy Increased risk of stroke in women over 35y/o Estrogens and oral contraceptives containing ethinyl estradiol are associated with several liver related complications including cholestatic jaundice (obstruction of bile exit portals in liver), sinusoidal dilation, peliosis hepatis, hepatic adenomas, hepatocellular carcinoma, hepatic venous thrombosis and an increased risk of gallstones. C-19 and C-21 progestins with C17-α–acetoxy substituents have also been known to induce cholestatic jaundice in rare instances ( with high doses formerly used in treating breast cancer) Some women appear to be have a genetic predisposition to cholestatic jaundice during first few cycles of O.C. use → further OC use is contraindicated Combination estrogen.& progestin reduce !! the risk of ovarian & endometrial cancer (even after stopping pills) May(??) be an increased risk of breast cancer in women who started O.C.’s at a younger age The daughters of women who used DES (no longer marketed) during pregnancy had a higher incidence of vaginal and cervical cancer For women who experience contraceptive failure, the risk of ectopic pregnancy ( fertilized egg implanting outside the uterus) may be greater than for women who do not use contraception. Ectopic pregnancy is very dangerous and is considered a medical emergency. Appendix The menstrual cycle: interrelationships between ovarian hormones and pituitary gonadotropins A. Pre-ovulatory (follicular phase): GnRH release from hypothalamus stimulates FSH release from the pituitary→ FSH stimulates growth and maturation of the follicle → the developing follicle secretes estrogen which is responsible for the proliferation of the endometrial lining → gradual suppression of FSH release from the pituitary as estrogen levels rise due to hypothalamic and/or pituitary estrogen-mediated negative feedback except at mid-cycle when negative feedback on pituitary by estrogen turns into positive feedback → mid-cycle surge in FSH and especially LH (LH surge) → FSH and LH surge produces ovulation. B. Post-ovulatory (luteal phase)—LH “luteinizes” the remnants of the ruptured follicle forming a corpus luteum → the corpus luteum synthesizes and secretes estrogen and (especially) progesterone; rising serum levels of both leads to a progressive feedback inhibition of FSH and LH secretion from the pituitary (meanwhile, the proliferation of the endometrial lining continues, however progesterone converts the endometrial lining to a more glandular appearance, and stimulates the formation of a secretory endometrium suitable for the implantation of a fertilized ovum) → the corpus luteum has a lifetime of approx. 14 days if fertilization and implantation of the ovum (i.e., pregnancy) doesn’t occur → in the absence of pregnancy, the corpus luteum atrophies (eventually becoming a non-functional “corpus albicans”) and estrogen and progesterone secretion ceases → Withdrawal (plummeting levels) of progesterone causes the sloughing off of the endometrial tissue (menstruation) and induces the synthesis of PGF α2 in the endometrial tissue →- PGFα2 is a prostaglandin which stimulates the myometrium (sometimes leading to cramping) and aids in the sloughing off of the endometrium. If pregnancy DOES occur, then the chorion layer of the developing syncytiotrophoblast (embryo) synthesizes and secretes hCG which maintains the corpus luteum far beyond its normal lifetime of 14 days. The corpus luteum continues to synthesize estrogen and progesterone for approximately the 1 st trimester of pregnancy at which point the placenta becomes responsible for the synthesis of these hormones. The relatively high levels of progesterone and estrogen in the serum during pregnancy exert negative feedback on the pituitary (and hypothalamus) such that no release of FSH or LH from the pituitary occurs, and consequently ovulation does not occur throughout the pregnancy. Hormonal Control of the Menstrual Cycle Effects of estrogen and progesterone on the endometrium Estrogen: 1. Proliferation of the endometrium 2. Promotes a watery secretion from the endometrium that sperm can easily migrate through. 3. Increases vascularization of the endometrium. Progesterone: 1. Slows the proliferation of the endometrium, but nonetheless it continues to proliferate 2. Converts the endometrium to a more glandular appearance. 3. Thick secretion of glycoproteins, amino acids, and carbohydrates (the glycoproteins form a mesh-like network) suitable for implantation of the fertilized ovum 4. Like estrogen, increases vascularization of the endometrium. Estrogens 1. Primary sources – developing ovarian follicle (granulsosa cells), corpus luteum, placenta. 2. Estradiol is the major secreted estrogen – in equilibrium with estrone in the circulation which is further metabolized in the liver to estriol (all three compounds have “estrogenic activity”) Estradiol – 80 X more potent than estriol Estrone – 7 X more potent than estriol 3. Estrone is the primary circulating estrogen after menopause → synthesized in adipose tissue by aromatization of androgens which have been released from the adrenal gland. 4. About 60% of the circulating estrogens are bound to a specific carrier protein, sex hormone-binding globulin (SHBG) or to albumin (about 20%) 5. Estrogens are metabolized in the liver to several metabolites which are excreted in the urine primarily as glucuronide metabolites. 6. Two different types of estrogen receptors have been identified: Alpha (α) receptors – expressed most abundantly in the female reproductive tract -- especially the uterus, vagina, and ovaries -- as well as in the mammary gland, the hypothalamus, and vascular smooth muscle Beta (β) receptors – expressed most abundantly in the ovaries and prostate, with lower expression in the lung, bone, brain, vasculature. This receptor is suggested to have a growth inhibitory role in prostate tissue Many cells express both ERα and ERβ Both estrogen receptors (ERs) are ligand-activated transcription factors that increase or decrease the transcription of target genes. After entering the cell by passive diffusion through the plasma membrane of target cells, estrogen binds to an ER in the nucleus. In the nucleus, the ER is present as an inactive monomer bound to heat shock protein 90 (HSP90), and upon binding estrogen, a change in the ER conformation dissociates the heat shock proteins allowing ER dimerization, which increases the affinity of the receptor for binding to “estrogen response elements” (EREs) on DNA. The dimerized estrogen receptor( with its two bound estrogens) can attract either co-activators to increase the transcription of a specific gene, or corepressors to inhibit the transcription of a specific gene. [FYI: The concept of ligand-mediated changes in ER conformation is central to understanding the mechanism of action of estrogen agonists and antagonists. The ER binds to estrogen response elements (EREs), located in the promoter region of target genes. The type of ERE with which ERs interact also regulates the conformation of the activated receptor. The ER/DNA complex recruits a cascade of co-activators and other proteins to the promoter region of target genes. Some of the coactivators have histone acetyltransferase activity, and acetylation of histones alters chromatin structure in the promoter region of targets genes and allows the proteins that make up the general transcription apparatus to assemble and initiate transcription. Interaction with antagonists also promotes ER receptor dimerization and DNA binding. However, an antagonist produces a conformation of ER that is different from the agonist-occupied receptor. The antagonist-induced conformational change facilitates binding of co-repressors. The co-repressor/ER complex then further recruits other proteins with histone deacetylase activity. Deacetylation of histones alters chromatin conformation and reduces the ability of the general transcription apparatus to from initiation complexes]. In the past, estrogen pharmacology was based on a simple model of an agonist binding to a single ER that subsequently affected transcription by the same molecular mechanism in all target tissues and of antagonists that acted by simple competition with agonists for binding. This simple concept is no longer valid. As described above, by altering the conformation of ERs and thereby changing interactions with co-activators and co-repressors in cell-specific and promoter-specific contexts, ligands may have a broad spectrum of activities from purely anti-estrogenic in all tissues, to partially estrogenic in some tissues with anti-estrogenic or no activities in others, to purely estrogenic in all tissues. The elucidation of these concepts has been a major breakthrough in estrogen pharmacology and should permit the rational design of drugs with very selective patterns of estrogenic activity (e.g., SERMS) 7. Primary physiological actions of estrogens i. development and maintenance of reproductive organs, including proliferation of the endometrial lining ii. development of female secondary sex characteristics iii. feedback modulation of pituitary gonadotropins sustained relatively-high levels inhibit FSH and LH release rapidly rising levels at midcycle (approx. day 14) stimulate LH release (i.e. positive feedback on the pituitary) iv. stimulation of growth and maturation of mammary glands v. CNS effects: influences reproductive behavior and general mood; may increase anxiety; may be neuroprotective & slow dementia vi. maintain structure of the skin and blood vessels in woman estrogens increase the synthesis of nitric oxide and prostacyclin which increases blood flow to the skin and counteracts the actions of thromboxanes → decreases total peripheral resistance vii. maintains bone structure inhibits resorption :↑’s apoptosis of osteoclasts and ↓’s apoptosis of osteoblasts and osteocytes inhibits actions of parathyroid hormone (PTH) increase synthesis of OPC (decoy receptor for RANKL) does not induce bone synthesis?? viii. increases hepatic synthesis of carrier proteins, particularly those for: vitamin D, cortisol, thyroid hormones ix. enhances coagulability of the blood by increasing the synthesis of: clotting factors II, VII, IX, X, XII x. changes composition of plasma lipids (most are beneficial): ↓ LDL ↑ LDL receptors ↑ HDL ↑ triglycerides and free and esterified cholesterol ↓ thromboxane effects on blood vessels ↑ prostacyclin production ↓ cholesterol deposition in vessels xi. Edema – estrogens makes blood vessels “leaky” allowing the loss of intravascular fluids into the extravascular tissues thereby producing edema as blood volume decreases there is a compensatory increase in Na+ and water retention due to increased aldosterone secretion and subsequent activation of the mineralocorticoid receptor xii. estrogens increase the synthesis of receptors for progesterone in the uterus Therapeutic Uses of Estrogens: 1. Alleviation of menopausal symptoms associated with estrogen deficiency (conjugated estrogens used most often) a. Women vary as to the extent they need replacement therapy, since body can synthesize estrone in adipose tissue from adrenal hormones. b. Replacement therapy can prevent: (i). Hot flashes and sweating The hot flash reaction occurs in response to an alteration in thermoregulatory control. The thermoregulatory centers in the hypothalamus are influenced by a number of neurotransmitters, including norepinephrine. Based primarily on animal studies, it has been hypothesized that estrogens stabilize the thermoregulatory center by preventing norepinephrine secretion into the hypothalamus. During perimenopause, the alteration in thermoregulatory control is believed to arise from a loss of, or diminished estrogen action on the hypothalamus, resulting in increased secretion of norepinephrine into the hypothalamus (ii). Atrophic vaginitis: Loss of tissue lining the vagina or bladder leads to a variety of symptoms in many postmenopausal women including dryness and itching of the vagina, painful sexual intercourse (dyspareunia), swelling of the tissues in the genital region, pain during urination, a need to urinate urgently or often, and sudden or unexpected urinary incontinence. The lower vaginal pH of the premenopausal woman allows for colonization of the vagina with lactobacillus, an organism that converts vaginal glycogen to lactic acid. Lactic acid serves to further reduce vaginal pH, which in turn inhibits vaginal colonization with harmful bacterial species. Vaginal pH: Premenopausal: 4.5 – 5 Postmenopausal: 6 – 8 c. Prolonged use of unopposed estrogen may increase risk of endometrial cancer → combined estrogen-progesterone replacement therapy may not only protect against the effect of estrogen, but may be protective in a general sense: (i). Addition of a progestin in women with an intact uterus is standard therapy to avoid consequences of unopposed estrogen therapy (specifically the increased risk of endometrial cancer). (ii). Estrogen is given for 21 – 30 days of the cycle, and usually, medroxyprogesterone (Provera) is added during the last 10 – 14 days of the cycle; this combination causes the return of regular menstrual periods which some postmenopausal women find objectionable; progestins alone or in combination with estrogen cause withdrawal bleeding in 80 – 90% of women. d. When estrogen is used alone, the lowest effective dose should be used for a limited time (cyclic administration seems best → give to mimic nature, first 21 to 25 days of the month; a vaginal ring is also useful. e. Hormone replacement therapy (HRT) is increasingly being discouraged in postmenopausal women due to a significant increase in the risk of breast cancer and an increased risk of myocardial infarction or stroke. Many clinicians recommend that the use of HRT should be limited to short-term use in women during menopause to treat menopausal symptoms such as hot flashes and urogenital symptoms 2. Dysmenorrhea – estrogen suppression of ovulation (3 weeks on – 1 week off regimen) 3. Failure of ovarian development – replacement therapy 4. Primary hypogonadism: estrogen therapy usually in combination with progesterone is instituted to stimulate development of secondary sex characteristics in young women (11 – 13 years of age) with hypogonadism 5. Acne – continual administration of combination estrogen/progestin oral contraceptives suppresses gonadotropin release from the pituitary, and consequently decreases ovarian androgen synthesis. 6. Post-menopausal osteoporosis – estrogens induce a positive Ca++ balance. a. Slows the process of osteoporosis → depends upon state of bone at menopause → only inhibits bone resorption (does not stimulate new bone synthesis ?? ) b. SERMS such as raloxifene (Evista®) and bazedoxifene/conjugated estrogens (Duavee®) are approved to treat osteoporosis (raloxifene) or prevent osteoporosis (raloxifene and bazedoxifene/con jugated estrogens) in post-menopausal women c. Estrogen deficiency as during menopause leads to a marked increase in bone resorption and a coupled increase in bone formation. However the increase in bone resorption outstrips the increase in bone formation, leading to net bone loss Adverse effects of estrogens 1. Nausea & vomiting are the most common adverse effects of estrogen therapy. 2. Breast tenderness, endometrial hyperplasia, and postmenopausal bleeding may occur → use smallest effective dose; unopposed estrogen causes withdrawal bleeding in 25% of women. 3. Hyperpigmentation (chloasma) – darkly-pigmented women are more susceptible. 4. Increased frequency of migraine headache 5. Increased frequency of hypertension – mainly with high potency, synthetic estrogens → increased renin substrate, increased aldosterone secretion. 6. Edema – leakage of vascular fluids into the tissues, and compensatory retention of Na+ and water. 7. Estrogens are contraindicated in patients with carcinoma of the breast and in patients with estrogen–dependent neoplasms (e.g. carcinoma of the endometrium) 8. Estrogen therapy decreases bile flow and increases the secretion of cholesterol into the bile, therefore estrogen therapy is associated with an increased frequency of cholelithiasis (gallstones) and gall bladder disease. 9. Diethylstilbestrol, DES, which was used from 1938 to 1971 to treat dysmenorrhea and threatened miscarriage, has been implicated as the possible cause of a rare, clear-cell cervical or vaginal carcinoma which has been observed in the daughters of women who took the drug during early pregnancy. (Note: DES was eventually found to be ineffecti ve in the treatment of threatened miscarriage) 10. Potential carcinogenic effects: -the use of unopposed estrogen for hormone treatment in postmenopausal women increases the risk of endometrial cancer by 5- to 15 fold -a small but significant increase in the risk of breast cancer has been found in postmenopausal women who received combined estrogen progesterone HRT apparently due to the medroxyprogesterone component; the increased risk required 3 or more years of treatment -the available data suggest that the excess risk of breast cancer abates 5 years after discontinuing therapy 11. Potential adverse cardiovascular effects: For many years it was believed that the combined progestin/estrogen hormone replacement therapy( HRT) used in the treatment of postmenopausal symptoms, was cardioprotective. However, in 2002, the results of a longterm study concluded that estrogen/ progestin combination HRT was not cardioprotective, but actually increased the risk of heart attack and stroke. Subsequent to this study, HRT use declined by 80% Progesterone 1. Primary sources: corpus luteum (granulosa cells), placenta Minor sources: ovary, adrenal cortex 2. Short plasma half-life, undergoes extensive first pass metabolism; metabolized in the liver to pregnandiol and excreted as glucuronide conjugate 3. Males and females produce about equal baseline amounts of progesterone 4. Physiological actions of progesterone: a. stimulates formation of an edematous, actively – secreting endometrium (after proper estrogen action) which is required for implantation of the fertilized ovum) → produces a mesh-like network of glycoproteins, amino acids, and carbohydrates b. maintenance of pregnancy – decreases the excitability of the myometrium and its sensitivity to oxytocin c. high plasma levels inhibit LH secretion from the pituitary d. Like all steroids, the receptor for progesterone is a nuclear transcription factor → its action on target tissues is due to stimulation of mRNA synthesis and consequent increase in protein synthesis e. progesterone competes with, and is an antagonist at aldosterone receptors; this action of progesterone counteracts somewhat the increase in Na + retention due to estrogen f. progesterone acts on the hypothalamus to raise body temperature 0.2 - 0.6 ºC; increase is observed for 4 days after ovulation g. effects on lipids (in general opposite to those of the estrogens): ↑ plasma LDL ↓ plasma HDL h. stimulates lipoprotein lipase (LPL) activity and seems to favor fat deposition ; however, conversely, progesterone also increases the utilization of fat as an energy source instead of glucose i. progesterone alters the function of respiratory centers - ventilatory response to CO2 is increased (synthetic progestins with an ethinyl group do not have respiratory effects) - leads to measurable reduction in arterial and alveolar pCO2 during pregnancy and the luteal phase of the menstrual cycle j. progesterone and some of its reduced metabolites(so-called “neurosteroids”) have depressant and anxiolytic/ hypnotic effects on the CNS k. progesterone is responsible for the alveolobular development of the secretory apparatus in the breast l. decreases the plasma levels of many amino acids and leads to increased urinary nitrogen excretion m. progesterone appears to normalize blood clotting n. improves vascular tone o. progesterone produced in the luteal phase of the menstrual cycle decreases the frequency of GnRH pulses arising from the hypothalamus. This progesterone- mediated decrease in GnRH pulse frequency is critical for suppressing gonadotropin release and is one of the mechanism of actions of the progestins found in contraceptives Therapeutic Uses for Progestins 1. Control of dysfunctional uterine bleeding (irregular, prolonged, severe uterine bleeding usually due to excessive secretion of estrogen → endometrial hyperplasia) the progestin stops the bleeding; upon discontinuation of the progestrin, a normal menstrual flow return s 2. Endometriosis ( dysmenorrhea often caused by retrograde menses resulting in growth of endometrial tissue in abnormal locations, e.g., intestine, bladder, fallopian tubes, ovary, rectum) → often associated with infertility due to a number of reasons including scarring of the ovary, blockade of fallopian tubes, others → continuous treatment with a progestin causes regression of the ectopic growth. 3. Contraception. 4. 1st generation C-19 synthetic progestins with androgenic activity appear to stimulate bone formation via their anabolic actions. 5. In combination with estrogens being used for hormone replacement therapy (HRT). Two major benefits of adding a progestin (usually medroxyprogesterone) are: - Decreased risk of estrogen-induced irregular bleeding. Protects against endometrial hyperplasia and carcinoma. 6. Levonorgestrel is used as so-called emergency contraception after known or suspected unprotected intercourse. The medication is given orally within 72 hours after intercourse as either a single 1.5 mg dose (PLAN B ONE STEP) or as two 0.75 mg doses (PLAN B) separated by 12 hours. The mechanism of action may involve several factors including prevention of ovulation, fertilization, and implantation. Adverse Effects of the Progestins: 1. Weight gain (↑’s lipoprotein lipase which leads to fat deposition), however weight gain is more prevalent with C-19 progestins with androgenic activity 2. Abdominal cramping, bloating 3. Depression and anxiety: associated primarily with the 17-alpha-acetoxy derivative, medroxyprogesterone (Provera), or the C-19 progestin, levonorgestrel 4. Acne – common with those 1st generation C-19 progestins which also possess androgenic activity. 5. ↑ LDL ↓HDL The 1st generation C-19 progestins may have more pronounced effects on plasma lipids because of their androgenic activity 6. Increased basal insulin levels and the insulin response to glucose. There is usually no manifest change in glucose tolerance. However, long-term administration of more potent progestins, such as norgestrel, may decrease glucose tolerance