Steroids Female Oral Contraceptives and Abortifacients By Judy

Steroids: Female Oral Contraceptives and Abortifacients By: Judy Garza

Topics Steroid Hormones Oral Contraceptives Abortifacient Ovulation Mechanism of Action: Oral Contraceptives Mechanism of Action: Abortifacients Male Hormonal Contraceptives Side Effects Future

Steroid Hormones Steroids that act as hormones. Grouped into five groups by the receptor to which they bind • Glucorticoids, mineralcorticoids, androgens, estrogens, and progestagens. Synthesized from cholesterol in the gonads and adrenal glands. Carried in the blood going to specific carrier proteins (ex. Sex hormone binding globulin or corticosteroid binding globulin).

How do steroid hormones work? In cytoplasm they can undergo an enzyme-mediated alteration like reduction, hydroxylation, or aromatization. The steroid binds to the specific receptor. The steroid receptor dimerizes The steroid-receptor ligand complex binds to specific DNA sequences and induces transcription of its target genes.

Oral Contraceptives Medications taken by mouth for the purpose of birth control. They are a class of synthetic steroid hormones that suppress the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior lobe of the pituitary gland. FSH and LH are called gonadotropic hormones and they stimulate the release of progesterone and estrogen from the ovaries which are responsible for modulating the menstrual cycle.

History of Oral Contraceptives 1500 years ago – papyrus inscriptions. Early 1900’s- Ludwig Haberlandt coined the term “hormonal sterilisation. ” Nov. 1921 - Haberlandt presented his work. 1927 - Haberlandt published 1929 - Adolf Butenandt isolated the first female sex hormone, estrone. 1934 - Butenandt isolated progesterone from pig ovaries.

History 1948 - Russel Marker synthesized progesterone using wild yam (Dioscorea). 1951 - Gregory Pincus, Margaret Sanger, et al. began researching. 1960 - 1 st pill introduced (Envoid 10 mg) 1970: Introduction low dose or second generation of OCS 1980: biphasic or triphasic regimens 1990: 3 rd generation OCS (O + P has less androgenic activity)

Abortifacients A substance that induces abortion. Controversy over the use of them. Types: • Herbal (ex. Brewer’s yeast, vitamin C, wild carrot, black cohosh, slippery elm, pennyroyal, nutmeg, mugwort, papaya, vervain, etc. ) • Pharmaceutical (Mifepristone and Misoprostol)

History of Abortifacients Ancient Greece – the colony of Cyrene had an economy based on silphium. All throughout history, herbs have been used as a means of abortifaceints. Modern days surgical methods and medications are used.

Ovulation Process in the menstrual cycle where a mature ovarian follicle ruptures and discharges an egg (ovum). Ovulation is triggered by a spike in the amount of Follicle-Stimulation Hormone (FSH)and Luteinizing Hormone (LH) released from the pituitary gland. Gonadoptopin releasing hormone (Gn. RH) stimulates the expression of LH and FSH.

Mechanism of Action: Oral Contraceptives Progesterone is the only naturally occurring progestagen. All have antiestrogenic and antigonadotropic properties. Differ in their affinity for progesterone receptors and side-effects. Only synthetic progestagens are used in oral contraceptives.

Mechanism for Oral Contraceptives Progesterone (aka Progestagen) Norethisterone Norethynodrel Synthetic Progesterones Levonorgestrel Chlormandinone acetate

Mechanism of Action: Oral Contraceptives Progestins There are two progesterone receptors: PR-A and PR-B. Both have AF-1 and AF-2 transactivation domains. Since the ligand-binding domains are identical, there is no difference in ligand binding. Upon binding to progesterone, the receptors are phosphorylated and form dimers that bind with high selectivity to progesterone response elements (PREs) located on target genes. Transcriptional activation occurs after recruitment of co-activators like SRC-1 in order to have histone acetylase activity. This increases the accessibility of general transcriptional proteins to the target promoter.

Gonadropinreleasing hormone Mechanism of Action: Oral Contraceptives Progestin-Only Contraceptive LH, FSH • In the stomach, ovulation is inhibited by suppressing function of the hypothalamic-pituitary-ovarian axis. • It then modifies the midcycle surges of luteinizing hormone (LH) and folliclestimulation hormone (FSH). • In the ovaries, hormone production is decreased. • There are modifications made to the ovaries that are unfavorable to implantation and the cervical mucus is thickened. • Also, it inhibits sperm action.

Mechanism of Action: Oral Contraceptives Estrogen • In oral contraceptives, the estrogens mainly used are mestranol and ethinyl estradiol. • It is produced in the ovaries by FSH and LH. • Too much estrogen cause side effects such as stroke, deep vein thrombosis, invasive breast cancer, heart attack, etc.

Mechanism of Action: Oral Contraceptives Estrogen Composed of 4 rings. The phenolic A ring is the principle structure that is responsible for selective, high-affinity binding to both receptors. Sterodial estrogens arise from androstendione or testosterone by aromatization of the A ring. Reaction is catalyzed by a cytochrome P 450 monooxygenase enzyme complex that uses NADPH and oxygen as co-substrates.

Mechanism of Action: Oral Contraceptives Estrogen Act primarily on the pituitary to control the amplitude of gonadtropic pulses and contribute to the amplitude of Gn. RH pulses secreted by the hypothalamus. They also inhibit gonadotropin (LH and FSH) release during the menstrual cycle, but then they have a mid-cycle stimulatory action that increases the amount released causing LH to surge.

Mechanism of Action: Oral Contraceptives Estrogen The hormone enters the cell and binds to an estrogen receptor (ESR 1, ESR 2). Binding causes a conformational change and causes receptor to dimerize which increases the affinity and rate of receptor binding to DNA. ER dimer binds to estrogen response elements located in the promoter region of target genes where it then can regulate many of the same target genes.

Mechanism of Action: Oral Contraceptives Estrogen + Progestins (aka Combination Oral Contraceptives) Progestins bind to albumin and sex hormone binding globulin in plasma then diffuse into cell cytoplasm Estrogen is lipid soluble and thus diffuses. Once in the cell, they regulate the transcription of specific genes in the uterus. Actions of hormones are mediated by their hormone receptors which are nuclear transpcription factors whose transcriptional regulartory activity is mediated by the binding of the specific steroid to these molecules. Once the receptors bind hormone, they bind to cis-acting sequences in the promoter region of responsive genes and regulate transcription of these genes.

Mechanism of Action: Oral Contraceptives Estrogen + Progestin (aka Combination Oral Contraceptives) The progestin negative feedback decreases the frequency of Gn. RH released. This decreases the release of FSH and LH which inhibit follicle development. Estradial levels do not increase (no positive feedback). In addition it decreases the amount of and viscosity of the cervical mucus, inhibiting sperm penetration. Estrogen also contributes to decreasing the amount of FSH produced by negative feedback on the anterior pituitary. No ovulation occurs as a result

Mechanism of Action: Oral Contraceptives Estrogen + Progestin (aka Combination Oral Contraceptives) • Monophasic • Same amount of estrogen and progestin in each active pill. • Classified by estrogen level • Low dose (20 mcg) • Regular dose (30 -35 mcg) • High dose (50 mcg) • Biphasic • Alter the level of hormones once during the menstrual cycle. • Same amount of estrogen but halfway through the cycle, progestin is increased. • Triphasic • 3 different doses of hormones. • Depending on brand, estrogen may increase.

Types of Oral Contraceptives Progesterone-Only • Evonid • Minipill Monophasic • Yasmin Biphasic • Necon Triphasic • Cyclessa (100 ug, 125 ug, or 150 ug desogesterl) • Ortho Tri-Cyclen Lo • Tri-Norinyl

Mechanism of Action: Abortifacients Mifepristone (aka RU-486) • It is a competitive receptor antagonist in the presence of • • progesterone at the progesterone receptor. It causes the decidual degeneration which leads to trophoblast detachment. Results in decreased production of Human chronic gonadotropin (h. CG), which causes decreased production of progesterone by the corpus luteum. Since pregnancy is dependant on progesterone production by the corpus lutenum, pregnancy is terminated. In addition it increases prostagladin release from the uterine lining, increasing uterine contractions and enhances the uterus’ sensitivity to prostagladin.

Mechanism of Action: Abortifacient Methotrexate • Blocks enzyme necessary for DNA synthesis, which inhibits the growth of placental trophoblastic cells.

Mechanism of Action: Abortifacient Misoprostol • Synthetic protaglandin E 1 analogue. • Used in combination with Mifepristone and Methotrexate. • Softens and dilates the cervix. • Binds to myometrial cells to cause uterine contractions which cause expulsion of the embryo.

Abortifacients Plan-B • Consists of two doses of the “minipill” (. 75 mg levonorgestrel per pill) separated by 12 hours. Preven (“Yuzpe”) • A two 2 -pill doses of a high-dose oral contraceptive (. 25 mg of levonorgestrel and. 05 mg of ethinyl estradiol per pill) separated by 12 hours.

Other Types of Contraceptives Vaginal rings • Nuvaring Transdermal • Contraceptive patches • Nestorone gel Intrauterine • Progestasert • Mirena Intramuscular • Gravibinon Subcutaneous • Norplant

Male Contraceptives Still in clinical trials. Stopping the secretion of a man’s reproductive hormones in the brain and the testes to reduce or block sperm is the ultimate goal.

Side Effects Blood clots Heart attacks Stroke Cancer Depression Nausea Dizziness Stomach upset Headache

Future Looking at reducing the risks involved with taking the pill. Using natural products. Vaccines

Refrences Matthiesson, Kati L. and Mc. Lachlan Robert. Male hormonal contraception: concept in sight? Human Reproduction Update, Vol. 12, No. 4 pp. 463– 482, 2006 Ferro, Valerie and Mann, Jamie. Recent Developments in Female Hormonal Contraception. Current Women’s Health Reviews, 2005, 1, 105 -118 Benagiano, Giuseppe, Bastianelli, Carlo and Farris Manuela. Contraception Today. ANNALS NEW YORK ACADEMY OF SCIENCES Orme, M. L’E. The Clinical Pharmacology of Oral Contraceptive Steroids. Br. J. clin. Pharmac. (1982), 14, 31 -42 Mears, Eleanor. Clinical Trials of Oral Contraceptives. British Medical Journal. Nov. 4. 1961 http: //www. contraceptiononline. org/contrareport/article 01. cfm? art=160 http: //www. nytimes. com/learning/general/onthisday/bday/0409. html http: //www. djerassi. com/CEcontraceptives/index. html