Photo: Color-enhanced scanning electron micrograph of a human oocyte. From: Seeley’s Anatomy & Physiology 10th ed New York, NY: McGraw-Hill 2010
Learning Objectives PHARMACOLOGY OF GONADAL HORMONES: 1. ESTROGENS AND PROGESTINS 1. The physiological actions and pharmacological effects of estrogens and progestins that are relevant to their clinical uses. 2. The adverse effects and contraindications of estrogens and progestins. 3. The current strategies for the use of estrogens and progestins in oral contraceptives and in hormone replacement therapy in menopause. 4. The pharmacological actions and clinical uses of Selective Estrogen Receptor Modulators (SERMs). 2. ANDROGENS 1. The physiological actions, pharmacological effects, and clinical uses of androgens. 2. The adverse effects and contraindications to use of androgens. 3. The pharmacology and clinical uses of androgen antagonists. Marc Imhotep Cray, MD
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Topical Outline
Organization and Function of Reproductive System Reproductive Pharmacology Overview GnRH, Gonadotropins and Related Agents Sex (Gonadal) Hormones and Antagonists Contraception Endometriosis and Treatment Combination Oral Contraceptives, and Progestin Postmenopausal Hormone Changes and Therapy Selective Estrogen Receptor Modulators and Antiestrogens Hypogonadism
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Gonadotropins & Related Drugs Follicle-stimulating hormone (FSH) Luteinizing hormone (LH) Chorionic gonadotropin Choriogonadotropin alfa Follitropin alfa Follitropin beta Urofollitropin GnRH analogs Leuprolide Goserelin Histrelin Ganirelix Marc Imhotep Cray, MD
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Sex hormones & Related Drugs ESTROGENS Estradiol USED IN MANY COMBINATIONS Estrone Ethinyl estradiol USED IN MANY COMBINATIONS Mestranol (w/norethindrone) SELECTIVE ESTROGEN-RECEPTOR MODULATORS (SERMs) Clomiphene Raloxifene Tamoxifen PROGESTOGENS Desogestrel USED IN MANY COMBINATIONS Drospirenone (w/ethinyl estradiol) Levonorgestrel Medroxyprogesterone Norelgestromin (w/ethinyl estradiol) Marc Imhotep Cray, MD
PROGESTOGENS cont. Norethindrone Norethindrone acetate Norgestimate USED IN MANY COMBINATIONS Norgestrel (w/ethinyl estradiol) Progesterone USED IN MANY COMBINATIONS Toremifene Dienogest (w/estradiol valerate) Etonogestrel (w/ethinyl estradiol) Etonogestrel (subdermal) PROGESTERONE AGONIST/ANTAGONIST Ulipristal acetate
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Sex hormones & Related Drugs cont. PROGESTERONE ANTAGONIST Mifepristone ANDROGENS Danazol Fluoxymesterone Methyltestosterone Oxandrolone Oxymetholone Testosterone Testosterone cypionate Testosterone enanthate Marc Imhotep Cray, MD
ANTIANDROGENS Bicalutamide Dutasteride Finasteride Flutamide Nilutamide
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Key Definitions & High-Yield Terms to Learn Androstanes: any 19-carbon steroid hormone, such as testosterone or androsterone, which controls the development and maintenance of male secondary sex characteristics Estranes: any 18-carbon steroid hormone, such as estradiol and estrone, produced chiefly by ovaries and responsible for promoting estrus and development and maintenance of female secondary sex characteristics Pregnanes: any 21-carbon steroid hormone, such as progesterone, responsible for changes associated with luteal phase of menstrual cycle, differentiation factor for mammary glands Cytochrome P450, CYP: any of a large number of enzymes produced from cytochrome P450 genes, are involved in synthesis and metabolism of various molecules Marc Imhotep Cray, MD and chemicals
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Steroid metabolism (steroidogenesis) Biosynthesis of steroids
P450scc
Enzymes with prefix CYP represent mitochondrial cytochrome P450 mixed function oxidases, and numbers indicate site of steroid hydroxylation. Steroids indicated in bold are primary secreted steroids.
Marc Imhotep Cray, Lynn MD Wecker et.al. Brody’s Human Pharmacology: Molecular to Clinical, 5th Ed. Philadelphia: Mosby, 2010
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Key Definitions & Term cont. Nuclear receptor: A superfamily of receptor molecules that are activated by steroid hormones, fatty acid derivatives, or products of metabolism such as bile acids. They act by altering rate of transcription of specific target genes. HREs: Hormone response elements. specific nucleotide sequences, residing upstream of steroid target genes, that are bound by steroid hormone receptors ERE: Estrogen-response element. A DNA sequence motif that binds estrogen receptors. Consensus sequence is GGTCANNNTGACC. PRE: Progesterone-response element. A DNA sequence motif that interacts with progesterone A or progesterone B receptors.
SERM: Selective estrogen receptor modulator. A group of drugs that display tissueCray, specific estrogen agonist or antagonist activity. Marc Imhotep MD
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Transcriptional regulation by intracellular steroid hormone receptors.
Whalen K. Lippincott Illustrated Reviews: Pharmacology, 6th Ed. Philadelphia, PA: Wolters Kluwer, 2015;352.
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Key Definitions & Term cont. 5α-Reductase The enzyme that converts testosterone to dihydrotestosterone (DHT)] 5α-Reductase is inhibited by finasteride, a drug used to treat benign prostatic hyperplasia (BPH) and prevent male-pattern hair loss in men Anabolic steroid Androgen receptor agonists used for anabolic effects (e.g., weight gain, increased muscle mass) Breakthrough bleeding Vaginal bleeding that occurs outside of period of regular menstrual bleeding Marc Imhotep Cray, MD
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Key Definitions & Term cont. Combined oral contraceptive (COC or just OC) Hormonal contraceptive administered orally that contains an estrogen and a progestin
Hirsutism A male pattern of body hair growth (face, chest, abdomen) in females that results from hyperandrogenism HRT (Hormone replacement therapy) refers to estrogen replacement for women who have lost ovarian function and nearly always involves combination therapy with estrogen and a progestin
Marc Imhotep Cray, MD
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Marc Imhotep Cray, MD
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Organization of Reproductive System Sex (gonadal) hormones include progestins, estrogens, and androgens Produced by gonads and adrenal glands necessary for conception, embryonic maturation, and development of primary and secondary sexual characteristics
One example of these functional gonadal relations is menstrual cycle: menstrual cycle is controlled by a neuroendocrine cascade involving hypothalamus, pituitary, and ovaries hypothalamus releases gonadotropin-releasing hormone (GnRH) triggers anterior pituitary to release gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) with effects on ovaries o N.B. Understanding menstrual cycle provides a basis for understanding pharmacology of contraception Marc Imhotep Cray, MD
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Organization of Reproductive System (2) Androgens are steroids w anabolic and masculinizing effects in both males and females Testosterone, main androgen in humans, is synthesized and secreted primarily by testicular Leydig cells, as well as by ovaries in women and by adrenal glands Testosterone secretion is also controlled by hypothalamuspituitary-gonad cascade
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Organization of Reproductive System (3) Microanatomy: Using Testis As Example Seminiferous tubules (3 cell types) Spermatogonia (germ cells) Line seminiferous tubules; Maintain germ pool and produce 1° spermatocytes Sertoli cells (non–germ cells) Line seminiferous tubules Secrete inhibin B inhibit FSH; Secrete androgen-binding protein maintain local levels of testosterone; Convert testosterone and androstenedione to estrogens via aromatase; Homolog of female granulosa cells Leydig cells (endocrine cells) Interstitium Secrete testosterone in presence of LH; Homolog of female theca interna cells
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated 16 Pharmacology, Updated Edition. Philadelphia: Sanders, 2014
Regulation of Estrogen and Testosterone Estrogen is synthesized in several forms, estradiol, estrone and estriol Potency: estradiol > estrone > estriol Many organs and processes in women are under influence of estrogen menstrual cycle shows its greatest effects For control of cycle hypothalamus periodically (pulsatile) releases GnRH triggers anterior pituitary to release gonadotropins= LH and FSH LH and FSH, are responsible for growth and maturation of ovarian follicles o also control ovarian production of estrogen and progesterone • exert feedback regulation on pituitary and hypothalamus and signal them when to start and stop releasing GnRH, FSH, and LH 17
Regulation of Estrogen and Testosterone (2) In males, hypothalamus and anterior pituitary also effect release of FSH (starts spermatogenesis) and LH (triggers steroidogenesis in Leydig cells) Testosterone resulting from steroidogenesis inhibits hormone production via negative feedback on pituitary and hypothalamus, and release of GnRH, FSH, and LH ends
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Regulation of Estrogen and Testosterone (3)
Marc Imhotep Cray, MD
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014
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Events of Normal Menstrual Cycle Understanding menstrual cycle provides a basis for understanding pharmacology of contraception
Start of cycle, cycle day 1, is arbitrarily defined as first day of menstruation In follicular (or proliferative) phase, hypothalamus releases GnRH triggers anterior pituitary to release LH and FSH These gonadotropins cause graafian follicle to mature and secrete estrogen Estrogen inhibits pituitary it reduces gland’s release of LH and FSH
(negative feedback loop) In midcycle, however, estrogen triggers a surge in gonadotropin release (LH surge) from pituitary (a brief positive feedback effect), which stimulates follicular rupture and ovulation Ruptured follicle becomes corpus luteum produces progesterone and Marc Imhotep Cray, MD under influence of LH during second half of cycle (luteal phase) estrogen
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Events of Normal Menstrual Cycle (2) Luteal (or secretory) phase Progesterone promotes development of a secretory endometrium that can accommodate embryo implantation Conception causes progesterone secretion to continue with endometrium maintained as suitable for pregnancy Without conception corpus luteum stops progesterone release and ceases to function hormone levels decrease and menstruation begins Marc Imhotep Cray, MD
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Events of Normal Menstrual Cycle (3)
28 days (normal range, 24–35 days) Follicular phase can vary in length Luteal phase is 14 days Ovulation day + 14 days = Menes
Follicular growth is fastest during 2nd week of follicular phase Estrogen stimulates endometrial proliferation Progesterone maintains endometrium to support implantation ↓Progesterone ↓fertility
Le T and Bhushan V. First Aid for the USMLE Step 1 2016 . McGraw-Hill 2016. 22
The Oocyte and Ovulation Developing follicle
Stages of oocyte development and ovulation
23 2011 Smith PR & Turek PJ. The Netter Collection of Medical Illustrations: Reproductive System, Volume 1, 2nd Ed. Philadelphia, PA: Saunders-Elsevier,
Smith PR & Turek PJ. The Netter Collection of Medical Illustrations: Reproductive System, Volume 1, 2nd Ed. Philadelphia, PA: Saunders-Elsevier, 2011 24
Menstrual cycle capsular summary: Menstrual cycle is divided into follicular phase and luteal phase Ovulation defines transition between these two phases During follicular phase, gonadotroph cells of anterior pituitary gland secrete LH and FSH in response to pulsatile GnRH stimulation Circulating LH and FSH promote growth and maturation of ovarian follicles Developing follicles secrete increasing amounts of estrogen At first, estrogen has an inhibitory effect on gonadotropin release Just before midpoint in menstrual cycle, however, estrogen exerts a brief positive feedback effect on LH and FSH release This is followed by follicular rupture and release of an egg into fallopian tube During second half of cycle, corpus luteum secretes both estrogen and progesterone Progesterone induces a change in endometrium from a proliferative to a secretory type If fertilization and implantation of a blastocyst do not occur within 14 days after ovulation corpus luteum involutes secretion of estrogen and progesterone declines, menses occurs, and a new cycle begins Cairo CW, Simon JB, Golan DE. (Eds.). Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. LLW, 2012.
Menstruation terminology Dysmenorrhea= Pain with menses often associated with endometriosis Oligomenorrhea > 35-day cycle Polymenorrhea < 21-day cycle Metrorrhagia= Frequent or irregular menstruation
Menorrhagia= Heavy menstrual bleeding > 80 mL blood loss or > 7 days of menses Menometrorrhagia= Heavy, irregular menstruation
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Marc Imhotep Cray, MD
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Reproductive Pharmacology Overview A number of diseases are treated pharmacologically via modification of reproductive hormone activity ranging from infertility and endometriosis to breast and prostate cancer Key concepts in this presentation will include: 1. Interactions between estrogen and pituitary gland 2. Effects of GnRH release frequency on gonadotropin release 3. Tissue selectivity of estrogen receptor agonists and antagonists 4. Strategies used to antagonize effects of endogenous sex hormones from suppression of hypothalamic-pituitarygonadal axis to antagonism at target tissue receptor Marc Imhotep Cray, MD
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Reproductive Pharmacology Overview (2) Sex hormones include androgens, progestins, and estrogens produced by gonads and adrenal glands (smaller quantities) They are necessary for: Conception Embryonic maturation, and Development of primary and secondary sexual characteristics during puberty Sex hormones are used therapeutically as contraceptives as therapy for menopausal Sx & postmenopausal complications as replacement therapy in hypogonadism several antagonists are effective in cancer chemotherapy Marc Imhotep Cray, MD
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Reprod Pharm Overview (3) Risks & benefits of estrogen postmenopausal w regard to cardioprotection neuroprotection, and carcinogenicity are a subject of much debate and considerable research Certain hormone-like drugs whose estrogenic activities are tissue selective (selective estrogen receptor modulators or SERMs) have different therapeutic uses, including prevention and treatment of breast cancer (tamoxifen) and osteoporosis (raloxifene) Marc Imhotep Cray, MD
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Reprod Pharm Overview (4) Infertility associated with anovulatory menstrual cycles can be treated by use of antiestrogens such as clomiphene In female patients with failure of ovarian development, therapy with estrogen, usually in combination with progestin, replicates most of the events of puberty Testosterone replacement therapy is used for male patients with hypogonadism Anti-androgens (flutamide) are used to treat androgendependent cancers such as prostate carcinoma Marc Imhotep Cray, MD
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Overview (5) reprod. pharm HY facts cont. Ways to achieve androgen deprivation The four ways to achieve androgen deprivation are: 1. Inhibition of pituitary gonadotropin release: GnRH analogs (leuprolide) 2. Inhibition of androgen synthesis: aminoglutethimide, ketoconazole, finasteride 3. Inhibition of androgen binding: androgen receptor blockers (flutamide and others) 4. Surgical extirpation of glands: castration and adrenalectomy
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Marc Imhotep Cray, MD
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Functional Gonadal Relations 3 gonadotrophic hormones of pituitary adenohypophysis (1)follicle-stimulating hormone (FSH) (2) luteinizing hormone (LH) of the female, known as interstitial cell–stimulating hormone (ICSH) in male, & (3)luteotropin (prolactin, LTH) These pituitary hormones determine development of M and FM gonads
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Functional Gonadal Relations (2) Germinal epithelia of testes and ovaries are responsible for production of sperm and ova, respectively Various stromal cells of gonads are responsible for production of androgen and estrogen hormones, which act on organs of reproductive tract, secondary sex organs, and other parts of body
There is a feedback loop for interdependent regulation of production of gonadal and pituitary hormones (See next slide) Marc Imhotep Cray, MD
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014
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Negative and Positive Feedback Regulation In most cases, a hypothalamic– pituitary–target gland axis is regulated by negative feedback whereby tropic hormone of anterior pituitary gland negative feedback effects on hypothalamus target gland hormone has negative feedback effects on both hypothalamus and anterior pituitary By way of these mechanisms levels of target gland hormone are maintained within normal physiological range
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Negative and Positive Feedback Regulation (2) Positive Feedback Although negative feedback is primary homeostatic mechanism in endocrine system, rare examples of positive feedback exist
Prime example of positive feedback occurs during menstrual cycle In late follicular phase of cycle, estradiol levels rise above a critical point above which positive feedback occurs o High estradiol concentration results in a surge in hypothalamic secretion of GnRH and pituitary secretion of LH (called LH surge) and FSH inducing ovulation • Ovulation and transformation of ovarian follicular cells into corpus Marc Imhotep Cray, MD luteum signals end of positive feedback
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Negative and Positive Feedback
Marc Imhotep Cray, MD
Mulroney SE & Myers AK. Netter's Essential Physiology 2nd Ed. Philadelphia: Elsevier, 2016.
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Gonadotropin-releasing hormone (GnRH) A decapeptide produced by neurons in preoptic area of hypothalamus Pulsatile secretion of gonadotropin-releasing hormone (GnRH) from hypothalamus is essential for release of gonadotropins-- follicle stimulating hormone (FSH) and luteinizing hormone (LH) --from anterior pituitary however, Continuous administration of GnRH inhibits gonadotropin release through down-regulation of GnRH receptors on pituitary Continuous admin. of synthetic GnRH analogs, such as o leuprolide o goserelin o nafarelin o Histrelin effective in suppressing production of gonadotropins • Several are available as implantable formulations that provide continuous delivery of drug Marc Imhotep Cray, MD
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Gonadotropin-releasing hormone (2) Suppression of gonadotropins leads to reduced production of gonadal steroid hormones (androgens and estrogens) Uses Thus, these agents are effective in treatment of prostate cancer endometriosis, and precocious puberty Adverse effects In women, GnRH analogs may cause hot flushes and sweating, diminished libido, depression, and ovarian cysts In men, initially cause a rise in testosterone that can result in bone pain Hot flushes, edema, gynecomastia, and diminished libido may also occur Contraindications Agents are contraindicated in pregnancy and breast-feeding Marc Imhotep Cray, MD
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Gonadotropin-releasing hormone agonists Gonadotropin-releasing hormone agonists (eg., leuprolide, goserelin) create a temporary medical oophorectomy by causing paradoxical effects on pituitary: initial stimulation of LH and FSH release and then (w continuous admin.) inhibition of hormone release o Effects result in reduced sex hormone levels and regression of endometriosis-related lesions Long-acting formulations are usually given every 28 days for approximately 6 months
Marc Imhotep Cray, MD
N.B. Remember that pulsatile administration of exogenous GnRH stimulates gonadotropin release, whereas continuous GnRH administration inhibits LH and FSH release and thereby blocks target cell function.
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Marc Imhotep Cray, MD
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014
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Gonadotropin-releasing hormone agonists (2) GnRH agonists are contraindicated in pregnancy
GnRH agonists have hypoestrogenic side effects, eg, mild bone loss (reverses after drug is stopped) b/c of concerns about osteopenia, add-back low-dose estrogen therapy has been used
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Gonadotropin-Releasing Hormone Antagonists Ganirelix, cetrorelix, and degarelix are synthetic peptides that act as competitive antagonists at GnRH receptors They dose-dependently inhibit secretion of FSH and LH Ganirelix and cetrorelix are used to inhibit premature LH surges in women undergoing ovarian hyperstimulation as part of infertility treatment Degarelix is indicated for treatment of advanced prostate cancer in men o By blocking pituitary GnRH receptors, inhibits secretion of gonadotropins and subsequent release of testosterone appears to be mechanism for suppression of cancer Absolute Contraindications All agents absolutely contraindicated for use during pregnancy (Category X) See U.S. FDA “CAT” System (Drug Use in Pregnancy Categories)
Adverse Effect major AE is hypersensitivity or allergic reactions, including anaphylaxis Marc Imhotep Cray, MD
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Question A 75-year-old man had surgery for prostate carcinoma, and local metastases were found intraoperatively. What is the most appropriate follow-up drug aimed at treating the metastases? A. Aminoglutethimide B. Fludrocortisone C. Leuprolide D. Mifepristone E. Spironolactone
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Answer Correct Answer is C. Leuprolide a peptide related to GnRH or luteinizing hormone-releasing hormone (LHRH), used to treat metastatic prostate carcinoma. By inhibiting gonadotropin release upon continuous administration it induces a hypogonadal state; testosterone levels in the body fall significantly, and this appears to be the mechanism for suppression of the cancer.
Incorrect Answers Explained Aminoglutethimide (A) is an aromatase inhibitor mainly used to treat Cushing disease (it inhibits synthesis of adrenal corticosteroids), and some patients with metastatic breast carcinoma. Fludrocorticone (B) is a mineralocorticoid used for chronic adrenal insufficiency (along with glucocorticoids) or congenital adrenal hypoplasia. Mifepristone (D) is an abortifacient/oxytocic drug. Spironolactone (E) is an aldosterone receptor blocker used mainly as for patients with primary or secondary hyperaldosteronism, and as an adjunct to management Marc Imhotep Cray, MDof severe heart failure. Classified as a potassium-sparing diuretic.
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Gonadotropins Gonadotropins Luteinizing hormone (LH) and Follicle-stimulating hormone (FSH) Structure LH and FSH are glycoproteins found in the anterior pituitary LH, FSH, and TSH are all composed of an identical α subunit and a β subunit unique to each hormone Actions and pharmacologic properties Activity of LH and FSH is mediated by specific membrane receptors that cause an increase in intracellular cAMP In women, LH o increases estrogen production in ovary and o is required for progesterone production by corpus luteum after ovulation FSH required for normal development and maturation of ovarian follicles Marc Imhotep Cray, MD
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Gonadotropins (2) In men, LH induces testosterone production by interstitial (Leydig) cells of testis FSH acts on testis to stimulate spermatogenesis and synthesis of androgen-binding protein Therapeutic uses FSH and LH of pituitary origin are not used pharmacologically Rather, menopausal and chorionic gonadotropins (described below) are used as source of biologically active peptides
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The hypothalamic-pituitary–reproduction axis.
Gonadotropins (3) In females, FSH stimulates ovarian follicle maturation and estrogen production, whereas LH assists FSH in follicle development, induces ovulation, and stimulates corpus luteum to produce progesterone and androgens In males, FSH stimulates spermatogenesis, whereas LH stimulates Leydig cells in testes to produce testosterone Cairo CW, Simon JB, Golan DE. (Eds.). Principles of Pharmacology: 49 The Pathophysiologic Basis of Drug Therapy. LLW, 2012.
Gonadotropins (4) LH and FSH have analogous but somewhat different effects in males and females Pertinent target cells in male are Leydig and Sertoli cells of testis, while Pertinent target cells in female are thecal and granulosa cells of ovary In each case, a two cell system is coordinated to mediate sex hormone actions “Two-cell systems for gonadal hormone action” (The next 2 slides illustrate and explain.) Marc Imhotep Cray, MD
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Gonadotropins (5) “Two-cell systems for gonadal hormone action” Male In male, binding of luteinizing hormone (LH) to the LH receptor (LH-R) activates testosterone synthesis in Leydig cells Testosterone then diffuses into nearby Sertoli cells, where binding of follicle-stimulating hormone (FSH) to its receptor (FSH-R) increases levels of androgen binding protein (ABP) ABP stabilizes high concentrations of testosterone that, together with other FSHinduced proteins synthesized in Sertoli cells, promote spermatogenesis in nearby germinal epithelium (not shown)
Cairo CW, Simon JB, Golan DE. (Eds.). Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. LLW, 2012. 51
Gonadotropins (6) “Two-cell systems for gonadal hormone action” Female In female, LH acts in an analogous manner to promote androgen (androstenedione) synthesis in thecal cells (Leydig cells equivalent) Androgen then diffuses into nearby granulosa cells, where aromatase converts androstenedione to estrone, which is then reduced to the biologically active estrogen, estradiol FSH increases aromatase activity in granulosa cells, promoting conversion of androgen to estrogen
Cairo CW, Simon JB, Golan DE. (Eds.). Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. LLW, 2012. 52
Le T and Bhushan V. First Aid for the USMLE Step 1 2016 . McGraw-Hill 2016.
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Normal FM internal genitalia, gross
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015. 54
Normal FM internal genitalia, radiograph
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
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Seminiferous tubules cells, function & location/notes
Le T and Bhushan V. First Aid for the USMLE Step 1 2016 . McGraw-Hill 2016.
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Normal testis, gross
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015. 57
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015. 58
Hypothalamic-Pituitary-Seminiferous tubules Axis
Le T and Bhushan V. First Aid for the USMLE Step 1 2016 . McGraw-Hill, 2016.
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Gonadotropins (7) Human menopausal gonadotropins (menotropins= hMG) and human chorionic gonadotropin (hCG) Menotropins are isolated from urine of postmenopausal women and contain a mixture of LH and FSH Urofollitropin is immunologically purified FSH from urine of pregnant women hCG is produced by placenta and can be isolated and purified from urine of pregnant women o hCG is nearly identical in activity to LH Recombinant human FSH (follitropin-α and follitropin-β are available) o less batch-to-batch variability than preps. derived from urine Recombinant LH is also available (Lutropin alpha)
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Gonadotropins (8) Menotropins and hCG Therapeutic uses Menotropins are used in concert with hCG to stimulate ovulation in women w functioning ovaries approx. 75% of women treated w these peptides ovulate hCG can be used in both men and women to stimulate gonadal steroidogenesis in cases of LH insufficiency hCG can be used to induce external sexual maturation and spermatogenesis in men w secondary hypogonadism o may require months of treatment for effect In absence of an anatomic block, hCG can promote descent of testes in cryptorchidism Marc Imhotep Cray, MD
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Gonadotropins (9) In women with infertility caused by failure to ovulate, hMG and hCG are used sequentially Injection of hMG (or FSH products) over of 5 to 12 days causes ovarian follicular growth and maturation, and subsequent injection of hCG ovulation occurs
Adverse effects Ovarian enlargement 20% of treated women ovarian hyperstimulation syndrome (OHSS) may be life threatening, up to 1% of pts, resulting in acute respiratory distress, ascites, hypovolemia, and shock Multiple births (5-10% of cases) Marc Imhotep Cray, MD
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Question You prescribe bromocriptine for a woman with primary amenorrhea. Normal menstruation returns about a month after starting therapy. Which statement best describes the mechanism by which bromocriptine caused its desired effects. A. Blocked estrogen receptors, enhanced gonadotropin release B. Increased follicle-stimulating hormone (FSH) synthesis C. Inhibited prolactin release D. Stimulated ovarian estrogen and progestin synthesis E. Stimulated gonadotropin-releasing hormone (GnRH) release
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Prolactin Review Source Secreted mainly by anterior pituitary • Structurally homologous to GH Function Stimulates milk production in breast, inhibits ovulation in females and spermatogenesis in males by inhibiting GnRH synthesis and release • Excessive amounts of prolactin associated with ↓ libido Regulation Prolactin secretion from anterior pituitary is tonically inhibited by dopamine from hypothalamus Prolactin in turn inhibits its own secretion by ↑ dopamine (DA) synthesis and secretion from hypothalamus • TRH ↑ prolactin secretion (e.g., in 1° or 2° hypothyroidism) Pharm DA agonists (e.g., bromocriptine) inhibit prolactin secretion and can be used in Tx of prolactinoma • DA antagonists (e.g., most antipsychotics) and estrogens (e.g., OCPs, pregnancy) 64 stimulate prolactin secretion
Prolactin Review (2)
Marc Imhotep Cray, MD
Le T and Bhushan V. First Aid for the USMLE Step 1 2016 . McGraw-Hill 2016.
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Question A 40-year-old woman with a history of schizophrenia is receiving treatment with risperidone, which has resulted in clinical improvement, including lessening of hallucinations. The patient lives in a group home and her compliance is monitored. She was brought to the hospital by her attendant with complaints of breast tenderness and no menstrual period for 3 months. The patient has a history of elevated cholesterol, which has been lowered in recent months with strict dietary modification, but otherwise has no chronic health issues. Her BMI (body mass index) is 26 kg/m2, down from 30 kg/m2 six months ago. Laboratory studies, including thyroid and pregnancy testing, are negative. Which of the following is the most likely explanation for this patient's amenorrhea? A. Drug-induced amenorrhea B. Polycystic ovary syndrome C. Primary ovarian insufficiency (premature ovarian failure) D. Schizophrenia E. Uterine fibroids F. Weight loss 66
Answer & Educational Objective A. Drug-induced amenorrhea Educational Objective: The secretion of prolactin is controlled by the inhibitory effect of hypothalamic dopamine. Hyperprolactinemia causes hypogonadism by inhibiting the release of gonadotrophin-releasing hormone from the hypothalamus. Risperidone and other antipsychotics cause hyperprolactinemia by their antidopaminergic action.
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Control of reproductive hormones
Marc Imhotep Cray, MD
Le T and Bhushan V. First Aid for the USMLE Step 1 2016 . McGraw-Hill 2016.
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Gonadal Hormones & Antagonists: Overview Sex hormones produced by gonads are necessary for Conception Embryonic maturation and Development of primary & secondary sexual characteristics at puberty Gonadal hormones are used therapeutically in Replacement therapy For contraception and Management of menopausal symptoms Several antagonists are effective in cancer chemotherapy All gonadal hormones are synthesized from precursor, cholesterol, in a series of steps that includes shortening of hydrocarbon side chain and hydroxylation of steroid nucleus Aromatization is last step in estrogen synthesis Marc Imhotep Cray, MD
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Synthesis of progestins, androgens & estrogens Progestins, androgens, and estrogens are steroid hormones derived from cholesterol Major progestins include progesterone and 17α-hydroxyprogesterone
Androgens include dehydroepiandrosterone (DHEA), androstenedione, and testosterone Estrogens include estrone and estradiol o Estrogens are aromatized forms of their conjugate androgens: • androstenedione is aromatized to estrone • testosterone is aromatized to estradiol
Cairo CW, Simon JB, Golan DE. (Eds.). Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. LLW, 2012.
Steroid hormone receptors Steroid hormone receptors (for gonadal steroids and adrenocortical steroids) are complex proteins inside target cell Steroid penetrates cell, binds to receptor and translocates into cell nucleus principal site of action where RNA synthesis occurs protein target tissue effect Compounds that occupy receptor w/o causing translocation into nucleus or replenishment of receptors act as antagonists, e.g. spironolactone to aldosterone cyproterone to androgens clomifene to estrogens Marc Imhotep Cray, MD
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A model of interaction of a steroid Sites and MOA Penetrating cell membrane, hormone combines with a cytoplasmic receptor exposes its DNA binding domain migrates to nucleus and binds to specific genes DNA mediated mRNA synthesis synthesis of functional proteins Steroidal hormones include:
Glucocorticoids Mineralocorticoid Androgens, Estrogens , Progestins Vitamin D & Thyroid Hormone Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilman’s
Marc Imhotep Cray, MD
The Pharmacological Basis of Therapeutics. 12th ed. McGraw-Hill, 2011
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Estrogens (prototype estradiol) Estradiol (aka 17β-estradiol) is most potent estrogen produced & secreted by ovaries It is principal estrogen in premenopausal women Estrone, a metabolite of estradiol, has approximately one-third estrogenic potency of estradiol Estrone is primary circulating estrogen after menopause generated mainly from conversion of androstenedione in peripheral tissues Estriol another metabolite of estradiol significantly less potent than is estradiol present in significant amounts during pregnancy, b/c it is principal estrogen produced by placenta Synthetic estrogens, such as ethinyl estradiol undergo less first-pass metabolism than do naturally occurring steroids and, thus, are effective when administered orally at lower doses Marc Imhotep Cray, MD
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Estrogen (2) Capsule Source Ovary (17β-estradiol), placenta (estriol), adipose tissue (estrone via aromatization) Potency: estradiol > estrone > estriol Function Development of genitalia & breast, FM fat distribution Growth of follicle, endometrial proliferation, ↑myometrial excitability Upregulation of estrogen, LH, and progesterone receptors Feedback inhibition of FSH and LH, then LH surge Stimulation of prolactin secretion ↑ transport proteins, ↑SHBG ↑HDL and ↓ LDL AllImhotep estrogens are derived from aromatization of precursor androgens Marc Cray, MD
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Estrogens (3) Estradiol Estrone Ethinyl Estradiol Estrogen Synthesis
Johannsen EC & Sabatine MS. PharmCards: Review Cards for Medical Students, 4th Ed. LLW, 2010.
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Estrogens (4) Mechanism: Bind to estrogen receptors (ERα and ERβ) & are transported into nucleus receptor–hormone complex binds to specific sequences of nucleotides (estrogen response elements) →↑transcription of certain genes Estrogen receptors found in FM reproductive tract, breast, pituitary, and hypothalamus Exogenous estrogens inhibit endogenous FSH secretion suppress ovulation Clinical Use: Oral contraceptives (with a progestin): inhibits ovulation, dysmenorrhea, polycystic ovarian disease (PCOD), primary hypogonadism Used for postmenopausal hormone replacement therapy to ↓ signs and symptoms caused by loss of ovarian function (vasomotor symptoms or “hot flashes,” genital atrophy, dryness etc.) and ↓ bone loss and fractures fallen out of favor b/c of cardiovascular adverse effects (more on this to follow) Marc Imhotep Cray, MD
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Estrogens (5) Adverse Effects: Postmenopausal uterine bleeding, hypertension, migraines, cholestasis, hepatic adenomas Estrogen-containing OCs increase risk of episodes of migraine headache
Endometrial hyperplasia, ↑ risk of endometrial cancer (if given w/o progestin) ↑ risk of breast cancer (if given w/ progestin) ↑ thromboembolic events, both arterial (MI, stroke) and venous (DVT, PE) Of note: Commercial estrogens include Estradiol, Estrone (Premarin), and Ethinyl Estradiol (Estinyl =most common estrogen in COCs) OCs are available in many estrogen plus progestin combinations Diethylstilbestrol (DES), a semisynthetic estrogen previously used during first trimester of pregnancy, was assoc. w infertility & ↑ incidence of vaginal & cervical clear cell adenocarcinomas in female offspring Marc Imhotep Cray, MD
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Clomiphene (Clomid) Antiestrogen (SERM) Mechanism: Antiestrogens interfere w binding of estrogen w its specific receptor, and also alter conformation of estrogen receptor such that it fails to activate target genes Binds to estrogen receptors (ERs) and competitively blocks binding of endogenous estrogens acts as an antagonist in hypothalamus and as a weak agonist in ovaries and endometrium Thus, has also been classified as SERM by some o Fulvestrant, by contrast, is a pure estrogen antagonist (all tissues) In premenopausal women: blockade at ER in anterior pituitary and hypothalamus → disrupt feedback inhibition to GnRH, FSH/LH secretion →↑secretion of GnRH, FSH/LH →↑gametogenesis & steroidogenesis in ovaries In postmenopausal women: little to no effect Marc Imhotep Cray, MD
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Clomiphene (2) Clinical Use: Treatment of female infertility (anovulation) Treatment of male infertility (oligozoospermia): success variable Adverse Effects: Multiple births Excessive enlargement of ovaries and ovarian cysts (caused by ↑ FSH and LH and a direct effect of clomiphene) Hyperstimulation syndrome: although multiple ovulation is common, in some patients, this is accompanied by an intense hypersensitivity (anaphylactoid) response Of note: fulvestrant (pure antiestrogen) may be indicated in Tx of ER-positive breast cancer resistant to tamoxifen Marc Imhotep Cray, MD
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Tamoxifen (Nolvadex) SERM Mechanism: A selective estrogen receptor modulator (SERM), exhibits tissuespecific pro-estrogenic and anti-estrogenic effects Binds to estrogen receptors (ERs) and competitively blocks binding of endogenous estrogens tamoxifen– ER complex alters estrogen-responsive gene expression Tamoxifen acts as an antagonist within breast (inhibiting cellular proliferation) and as an agonist within bone (exerting an antiresorptive effect) and uterus (inducing cellular proliferation) b/c it is an agonist in uterus associated w increased risk of endometrial hyperplasia and cancer
Clinical Use: Endocrine treatment of both early and metastatic ER-positive breast cancer in both pre- and postmenopausal women May be useful in chemoprevention of breast cancer in women at high risk Reduces severity of osteoporosis (but not used for this indication b/c of availability of agents w superior side effect profiles) Marc Imhotep Cray, MD
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Tamoxifen (2) Adverse Effects: Hot flashes, menstrual irregularities, vaginal bleeding and discharge, nausea, vomiting ↑ risk of endometrial cancer Venous thromboembolic events (DVT, PE) Of note: toremifene SERM with tissue specificities similar to tamoxifen raloxifene SERM that is an antagonist in breast and uterus and an agonist in bone o It is used to treat postmenopausal osteoporosis o Not associated w ↑ risk of endometrial cancer but is assoc. w DVT and PE (albeit, less than tamoxifen) NB: Compared w tamoxifen, raloxifene is as effective in preventing invasive breast cancer (although less effective in preventing carcinoma in situ) and is less likely to cause endometrial cancer or DVT/PE Marc Imhotep Cray, MD
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Selective Estrogen Receptor Modulators SERMs are hormone-like drugs with tissue-selective estrogenic activities
Act as competitive antagonists or weak agonists: estrogenic in bone but no effect or antagonistic in breast and endometrium Tamoxifen, first classed as antiestrogenic is used to prevent and treat hormone-responsive breast cancer inhibits cell proliferation and reduces tumors as a result of estrogen receptor antagonism It has estrogenic actions in uterus stimulates endometrial proliferation and thickening increases carcinoma risk and In skeletal reduces bone loss In cardiovascular systems improves lipid profiles Adverse effects Hot flashes, menstrual abnormalities, thrombosis, and pulmonary embolism
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SERMs (2) Raloxifene is used to prevent and treat osteoporosis: Estrogen agonist action in bone and on lipid metabolism Estrogen antagonist action in breast and uterus o it is antiproliferative for estrogen positive breast cancer cells o lowers risk of breast cancer in high-risk women o does not result in ↑ incidence of endometrial cancer (such as estrogen and tamoxifen do) o lowers LDL cholesterol Adverse effects hot flashes, leg cramps, and venous thromboembolism Marc Imhotep Cray, MD
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SERMs
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Antiestrogens Antiestrogens are distinguished from SERMs in that they act as pure antagonists in all tissues Fulvestrant, for example, is a pure estrogen antagonist (all tissues) The antiestrogen clomiphene binds competitively to estrogen receptors and decreases sites available to endogenous estrogen including hypothalamic and pituitary estrogen receptors This inhibition leads to a disruption in negative feedback of estrogens on hypothalamus and pituitary a subsequent ↑ in secretion of GnRH and gonadotropins, and ultimately stimulation of ovulation Used to treat infertility associated with anovulatory menstrual cycles but it is effective only in women with a functional hypothalamus and adequate endogenous estrogen production Adverse effects clomiphene are dose related , include ovarian enlargement, vasomotor symptoms, visual disturbances and (multi-birth pregnancy ) Marc Imhotep Cray, MD
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Clomiphene MoA Illust. Clomiphene acts by inhibiting negative feedback effects of estrogen at hypothalamic-pituitary levels, increasing follicularstimulating hormone (FSH) concentrations and thereby enhancing follicular maturation Remember clomiphene is a weak agonist in ovaries & endometrium Thus, has also been classified as SERM by some Marc Imhotep Cray, MD
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Anastrozole (Arimidex) aromatase inhibitor Mechanism: Competitive inhibitor of aromatase final enzyme complex in synthesis of estradiol and estrone from androgens androstenedione and testosterone, respectively Clinical Use: Used in postmenopausal women with an ER−positive breast cancer when tamoxifen is contraindicated or has proven ineffective In some clinical trials, efficacy shown to be superior to SERMs in premenopausal women, normal ovarian function leads to a counterproductive feedback loop: ↓ estrogens → compensatory ↑ gonadotropins → ↑ ovarian androgen synthesis and aromatase expression →↑estrogen Adverse Effects: Arthralgias, myalgias, ↓ bone mineral density w ↑ risk of osteoporosis (mediated by blocking beneficial estrogen effects on bone) NB: Unlike tamoxifen, no endometrial cancer or thromboembolic events Marc Imhotep Cray, MD
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Anastrozole (2)
Johannsen EC & Sabatine MS. PharmCards: Review Cards for Medical Students, 4th Ed. LLW, 2010.
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Estrogens estradiol and estrone from Androgens androstenedione and testosterone
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Aromatase inhibitors (3) Of note: letrozole and exemestane are other aromatase inhibitors, w latter being an irreversible inhibitor Utility of aromatase inhibitors for chemoprevention of breast cancer is under study
Aminoglutethimide was first clinically used aromatase inhibitor It also blocks cholesterol → pregnenolone, first step in adrenal steroid synthesis Used to treat prostate cancer, breast cancer, Cushing’s syndrome, and adrenal tumors has fallen out of favor b/c of its nonselectivity
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Progesterone Progesterone, the natural progestogen, is produced in response to luteinizing hormone (LH) by both females (secreted by corpus luteum during second half of menstrual cycle, and by placenta) and by males (secreted by testes) It is also synthesized by adrenal cortex in both sexes Progestins (=synthetic progestogens) generally exert antiproliferative effects on female endometrium by promoting endometrial lining to secrete rather than proliferate Marc Imhotep Cray, MD
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Progestogens Mechanism of Action Progestogens exert their MOA in a manner analogous to other steroid hormones (activation of SRE→↑genes transcription) In females promotes development of a secretory endometrium that can accommodate implantation of a newly forming embryo high levels of progesterone released during second half of menstrual cycle (luteal phase) inhibit production of gonadotropin prevent further ovulation If conception takes place progesterone continues to be secreted, maintaining endometrium in a favorable state for continuation of pregnancy and reducing uterine contractions If conception does not take place release of progesterone from corpus luteum ceases abruptly decline stimulates onset of menstruation Marc Imhotep Cray, MD
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Progestins (synthetic progestogens) Mechanism of Action: Regulate transcription: bind to progestin receptor →activation of steroid response elements →↑transcription of certain genes RNA synthesis protein synthesis target tissue effect Progesterone (major naturally occurring progestin in humans) causes o development of secretory tissue in breast o maturation of uterine endometrium, and o can inhibit GnRH, FSH, and LH secretion Marc Imhotep Cray, MD
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Progestins (2) Clinical Use: Contraception Prevent ovulation by inhibiting midcycle LH/FSH surge Create suboptimal endometrial environment for implantation Makes cervical mucus “hostile” to sperm disrupt uterine & tubal motility Given with estrogens as part of postmenopausal hormone replacement therapy to ↓ endometrial hyperplasia and risk of endometrial cancer Dysfunctional uterine bleeding (DUB, usually due to continuous estrogen production w/o progesterone) Endometriosis: progestins can prevent proliferation of ectopic endometrial tissue Bleeding Fibroid Tumors: Progestins (medroxyprogesterone) can partially suppress estrogen stimulation in turn can decrease fibroid growth and vaginal bleeding Withdrawal bleeding: a diagnostic test used to evaluate amenorrhea Menstruation after cessation of progestin therapy suggests uterus has been primed by endogenous estrogens 95
Progestins (3) Adverse Effects: Hypertension* (but less so than estrogen) May ↓ HDL Weight gain hypermenorrhea N.B. *Drospirenone =only progestin drug with antihypertensive properties. Structurally related to spironolactone and acts as an aldosterone receptor antagonist. Therefore, it causes an increased renal sodium excretion, which can account for its diuretic and antihypertensive effects. Marc Imhotep Cray, MD
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Androgens (Prototype testosterone) Androgens are a group of steroids that have anabolic and/or masculinizing effects in both M and FM Testosterone, most important androgen in humans, is synthesized by Leydig cells in testes thecal cells in ovaries (smaller amounts) and adrenal gland in both sexes Other androgens secreted by testes are 5α-dihydrotestosterone (DHT), androstenedione, and dehydroepiandrosterone (DHEA) in small amounts In adult males, testosterone secretion by Leydig cells is controlled by GnRH from hypothalamus stimulates anterior pituitary gland to secrete FSH and LH
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N.B. Testosterone is essentially a prohormone only modest affinity for androgen receptor. Test. is converted in target tissues to more active DHT (dihydrotestosterone) which binds to androgen receptor with an affinity ten times higher than that of testosterone.
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Pathway of synthesis of testosterone in the Leydig cells of the testes In Leydig cells, 11 and 21 hydroxylases (present in adrenal cortex) are absent but CYP17 (17 αhydroxylase) is present thus androgens & estrogens are synthesized/ but corticosterone & cortisol are not formed Bold arrows indicate favored pathways.
Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. McGraw-Hill, 2011
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Direct effects of testosterone and effects mediated indirectly via DHT or estradiol
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Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilmanâ&#x20AC;&#x2122;s The Pharmacological Basis of Therapeutics. 12th ed. McGraw-Hill, 2011
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Androgens (3) Mechanism: Binds to cytosolic receptor taken into nucleus activates transcription of testosterone responsive genes In skin, prostate, seminal vesicles, and epididymis, testosterone is converted by 5-α reductase to more potent dihydrotestosterone Physiologic effects: ↑overall body growth (↑ protein synthesis and ↓ protein breakdown), penile and scrotal growth, development of secondary sex characteristics ↑ RBC production: secondary to both ↑ erythropoietin production by kidney and direct stimulation of Epo-sensitive elements in bone marrow Also, ↑ erythrocyte 2,3-DPG levels hence ↑ availability of oxygen Clinical Use: Replacement therapy in hypogonadism Anabolic agent (frequently abused) Marc Imhotep Cray, MD
Primary testicular failure such as result of bilateral anorchia, Klinefelter’s (XXY) karyotype, surgery, chemotherapy and radiotherapy, or secondary testicular failure as a result of hypothalamic– pituitary disease.
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Androgens (4) Adverse Effects: Men: acne, gynecomastia, testicular atrophy caused by suppression of gonadotropins, azoospermia, prostatic hypertrophy, physical aggression Women: masculinization Cholestatic jaundice, ↑ transaminases, hepatocellular carcinoma o 17α-alkylated androgens are only androgens that cause hepatotoxicity Of note: methyltestosterone (android) and fluoxymesterone are similar agents oxandrolone and nandrolone are anabolic steroids that are structurally similar to testosterone and act as androgen receptor agonists o can facilitate weight gain o prior to development of recombinant erythropoietin, were used to treat anemia of chronic kidney disease Marc Imhotep Cray, MD
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Androgens (5) Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) and androstenedione are adrenal steroids that are androgen precursors DHEA and DHEAS have been marketed as dietary supplements to improve strength, well-being, cognition & libido (little data to support these claims) have been abused by professional athletes as an alternative to anabolic steroids Androstenedione was a dietary supplement used, most notably, by Major League Baseball players as a performance enhancing drug it has since been banned
Johannsen EC & Sabatine MS. PharmCards: Review Cards for Medical Students, 4th Ed. LLW, 2010.
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Flutamide (Eulexin) Anti-androgen Mechanism: An anti-androgen, competitive antagonist at androgen receptor Prostate growth depends on androgens so androgen deprivation ↓ progression of prostate cancer o Flutamide does not affect testosterone production by Leydig cells Clinical Use: Androgen deprivation therapy in prostate cancer, both for locally advanced disease (in conjunction w radiation therapy or surgery →↑survival) and for metastatic disease (alleviate bone pain; modest survival benefit) It is used combination with GnRH agonists (e.g., leuprolide) o N.B. has limited efficacy when used alone b/c it ↑ LH secretion that stimulates higher serum testosterone concentrations Side Effects: Gynecomastia, Hepatitis Of note: bicalutamide and nilutamide are similar androgen receptor blockers cyproterone is an anti-androgen w progestogenic effects that is used in women to ↓ hirsutism and in men to ↓ sexual drive (hypersexuality) Marc Imhotep Cray, MD
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Flutamide (2)
Johannsen EC & Sabatine MS. PharmCards: Review Cards for Medical Students, 4th Ed. LLW, 2010. Marc Imhotep Cray, MD
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Finasteride (Proscar) Anti-androgen Mechanism: 5α-reductase inhibitor that blocks conversion of testosterone to more potent dihydrotestosterone (DHT) DHT is the principal androgen that acts on prostate Clinical Use: Benign prostatic hyperplasia (BPH): ↓ prostate size and hence obstructive symptoms of BPH such as difficulty in initiating voiding, ↓ caliber and force of urinary stream, sensation of incomplete emptying, and frequent urination May take 6–12 months to have a noticeable effect Androgenetic alopecia (male pattern baldness) Adverse Effects: Loss of libido, erectile dysfunction Contraindication: teratogenic & can be absorbed through skin women who may be pregnant should not take or handle crushed or broken tablets Marc Imhotep Cray, MD
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Finasteride (2)
Johannsen EC & Sabatine MS. PharmCards: Review Cards for Medical Students, 4th Ed. LLW, 2010. Marc Imhotep Cray, MD
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Finasteride (3) Of note: dutasteride is a related inhibitor of 5α-reductase used for male androgenetic alopecia and BPH Utility of 5α-reductase inhibitors in prevention of prostate cancer remains controversial o ↓ overall incidence of prostate cancer but ↑ risk that tumors that do develop are high grade o no effect on mortality α-blockers are also used to treat BPH (e.g., prazosin)
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Question A 66-year-old Caucasian male is treated with flutamide for metastatic prostatic cancer. He experiences significant relief of his bone pain soon after initiation of the therapy. The primary tumor decreases in size. Which of the following is the best explanation for the changes observed in this patient? A. Decreased Leydig cell stimulation B. Decreased Leydig cell androgen synthesis C. Decreased peripheral androgen aromatization D. Decreased peripheral androgen conversion E. Impaired ligand-receptor Interaction
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Answer & Educational Objective E. Impaired ligand-receptor Interaction Educational Objective: Flutamide is a non-steroid anti-androgen that competes with testosterone and DHT for testosterone receptors It is used for treatment of prostate cancer in combination with GnRH agonists
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Incorrect Answers Explained (Choice A) Gonadotropin-releasing hormone (GnRH) agonists (leuprolide, goserelin, nafarelin and histrelin) bind to GnRH receptors in anterior pituitary and inhibit synthesis of LH and FSH, if administered continuously o Decreased amount of LH leads to decreased Leydig cell stimulation and diminished testosterone synthesis (Choice B) Ketoconazole is a weak antiandrogen that decreases synthesis of steroid hormones in gonads and adrenals (Choice C) Decreased peripheral androgen aromatization refers to mechanism of anastrozole, a nonsteroidal aromatase inhibitor which blocks estrogen production selectively o Anastrozole is an effective treatment for postmenopausal women with breast cancer in whom the greatest source of estrogen is the conversion of androstenedione, produced in adrenal glands, to estrone in liver, muscle, and fat, through aromatization (Choice D) Finasteride decreases peripheral conversion of testosterone into dihydrotestosterone by inhibiting the 5-α-reductase o It is used for treatment of BPH and male baldness Endocrine Pharm. UWorld, 2014.
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Combination Oral Contraceptives (COCs) ď ą COCs contain both estrogen and progestin and prevent pregnancy through two main mechanisms 1. They inhibit ovulation (most important ) via a negative feedback mechanism on hypothalamusď&#x192; which alters normal pattern of FSH and LH secretion by anterior pituitary o Estrogen suppresses FSH release from pituitary during follicular phase of menstrual cycle and inhibits midcycle surge of gonadotropins o Progestin inhibits estrogen-induced LH surge 2. thicken cervical mucus, thus providing a physical barrier that slows or stops sperm motility (progestin component) Marc Imhotep Cray, MD
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COCs (2) COCs also produce alterations in genital tract Progestin responsible for changing cervical mucus and rendering it unfavorable for sperm penetration even if ovulation occurs
COCs induce an environment in endometrium that is unfavorable for implantation COCs may also alter tubal transport of sperm, egg, and fertilized ovum through fallopian tubes Marc Imhotep Cray, MD
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COCs (3)
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Major Adverse Effects of COCs Major effects, of excess or lack of estrogen or progestin, include breast fullness depression dizziness edema migraine and cluster headaches, and vomiting Serum lipoprotein profiles can change: estrogen increases HDL levels and decreases LDL levels progestins (esp. norgestrel) cause unwanted opposite effect o decreases HDL levels and increases LDL levels Marc Imhotep Cray, MD
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Major Adverse Effects of COCs (2) COCs are associated with
gallbladder disease cholestasis abnormal glucose tolerance hypertension and thromboembolic disorders (estrogen component)
COCs are contraindicated if pt. has
cerebrovascular and thromboembolic disease estrogen-dependent neoplasms abnormal genital bleeding chronic diabetes, or liver disease
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Adverse Effects of COCs (3)
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Benefits COCs Benefits include reduced risk of ovarian cysts benign breast disease, and ectopic pregnancy improved premenstrual symptoms dysmenorrhea endometriosis acne and hirsutism COCs reduce endometrial and ovarian tumor incidence their cause of other neoplasms is controversial Marc Imhotep Cray, MD
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COCs Drug-Drug Interactions Cytochrome P-450 enzyme inducers (e.g. chronic alcohol use phenytoin, phenobarbital, rifampin, carbamazepine) enhance hepatic metabolism of oral contraceptives (especially estrogen component) leading to reduced contraceptive levels and unintended pregnancy (contraceptive failure) P-450 enzyme inducers also interacts by inducing synthesis of hormonebinding globulins more hormone molecules are bound to protein, and so less free (active) drug is in circulation Some antibiotics (e.g., tetracyclines) interact w OCs mechanism: antibiotics suppress gut flora that participate in enterohepatic recycling of OCs When bacteria are suppressed OCs secreted into gut are lost in feces, rather than being reabsorbed Marc Imhotep Cray, MD
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Skill Keeper: Cytochrome P450 & Hormonal Contraceptives Hormonal contraceptives usually contain lowest doses of estrogen and progestin components that prevent pregnancy Margin between effective and ineffective serum concentrations of steroids is narrow which presents a risk of breakthrough bleeding and also unintended pregnancy resulting from drug–drug interactions Most steroidal contraceptives are metabolized by cytochrome P450 isozymes 1. How many drugs can you identify that decrease the efficacy of hormonal contraceptives by increasing their metabolism? 2. When one of these drugs is prescribed for a woman who already is using a combined hormonal contraceptive, what should be done to prevent pregnancy? 120
Skill Keeper Answers: CYP P450 and Hormonal Contraceptives 1. Gonadal steroids and their derivatives are metabolized primarily by cytochrome P450 3A4 (CYP3A4) family of enzymes Inducers of CYP3A4 include barbiturates, carbamazepine, corticosteroids, griseofulvin, phenytoin, pioglitazone, rifampin, and rifabutin. potential reduction in contraceptive efficacy of OCs by carbamazepine and phenytoin are of particular importance because these drugs are known teratogens St. John’s wort, an unregulated herbal product, contains an ingredient that induces CYP3A4 enzymes and can reduce the efficacy of hormonal contraceptives.
2. To prevent an unwanted pregnancy, it would be advisable to use a COC pill with a higher dose of estrogen (e.g., a formulation containing 50 mcg of ethinyl estradiol). Alternatively, or additionally, women may use a barrier form of contraception or switch to an IUD. 121
Estrogen and Coagulation Estrogens may affect fibrinolytic pathways and cause ↑ in coagulation factors II, VII, VIII, IX, X, and XII (the main action) and ↓ in anticoagulation factors N.B. These actions augment risk of o protein C thromboembolic disease in women o protein S taking COCs about threefold compared o plasminogen activator inhibitor protein I to women taking no hormones. o antithrombin III By causing imbalance between coagulation and anticoagulation, estrogens may produce serious associated complications, including thromboembolism thrombophlebitis myocardial infarction, and cerebral and coronary thrombosis These complications are more likely to occur in women who Marc Imhotep Cray, MD smoke and are older than 35 years
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Estrogen and Coagulation (2)
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Estrogen and Coagulation (3)
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014
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Progestin-Only Contraceptives Progestin thickens cervical mucus (decreases sperm penetration) and alters endometrium thus preventing implantation
Progestin-only formulations are available as pills (“minipills”), depot injections, and implants Pills contain norethindrone or norgestrel, taken daily on a continuous schedule o less effective than COCs b/c they block ovulation in only 60% to 80% of cycles
Absence of estrogen also lowers risk of thromboembolic disorders a major advantage, especially, for women who smoke Marc Imhotep Cray, MD
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Progestin-Only Contraceptives (2) Depot injections of medroxyprogesterone acetate (MPA) impair implantation and produce plasma drug levels high enough to prevent ovulation in virtually all pts by slowing GnRH release thus prevents LH surge required for ovulation Progestin implants (subdermal capsules containing levonorgestrel) offer contraception for approximately 5 years
Nearly as effective as sterilization, w completely reversible effects if implants are surgically removed Note: Levonorgestrel is also an effective postcoital contraceptive Adverse effects o ↑ appetite & weight gain o breast tenderness o headaches, and o frequent occurrence of irregular menstrual bleeding Marc Imhotep Cray, MD
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Progestin-Only Contraceptives (3)
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Morning After Pill (Emergency contraception) Postcoital (or emergency) contraceptives consist of high-dose estrogen (ethinyl estradiol), administered within 72 hours of coitus and continued twice daily for 5 days Alternatively, 2 doses of ethinyl estradiol plus norgestrel can be used within 72 hours of coitus- followed by another 2 doses 12 hrs. later An alternative emergency contraceptive is progesterone agonist/antagonist ulipristal indicated for contraception within 4-5 days of unprotected intercourse
Emergency contraception does not interrupt an established pregnancy, which officially begins w implantation Emergency contraceptives are associated w a high incidence of N/V b/c of high doses of hormones used Marc Imhotep Cray, MD
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Emergency contraception(2) Both ethinyl estradiol and norgestrel may inhibit or delay ovulation if taken during first half of cycle alter endometrial receptivity for implantation interfere w Fx of corpus luteum that maintains pregnancy decrease sperm penetration affect fertilization, and alter transport of sperm, egg, or embryo
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Morning After Pill (3)
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“The Abortion Pill” [Mifepristone (RU-486)] Mifepristone (RU-486) a progestin antagonist w partial agonist activity (an abortifacient/oxytocic drug) Use Medical termination of intrauterine pregnancy through 49 days gestation MOA Taken early in pregnancy, mifepristone interferes w progesterone causing a decline in human chorionic gonadotropin (hCG) and subsequent abortion of fetus Mifepristone also sensitizes endometrium to prostaglandins terminate gestation by inducing uterine contractions o Therefore, it is rational to use mifepristone w prostaglandin misoprostol (PGE1 analog), esp. b/c mifepristone alone is more likely to cause an incomplete abortion Marc Imhotep Cray, MD
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Mifepristone (2) Dosing Regimen consists of a single dose of mifepristone, followed by a single dose of misoprostol 2 days later Adverse Effects ď&#x201A;§ Expected major adverse effects are cramping and bleeding, which are similar to symptoms of a spontaneous abortion ď&#x201A;§ Incomplete abortion is also possible Marc Imhotep Cray, MD
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COCs and Progestins COCs and progestins also suppress LH and FSH so they render endometrial tissue thin and compact thus alleviating endometriosis COCs can be taken continuously or cyclically
Therapy can be stopped after 6 to 12 months or continued indefinitely Progestins may have greater adverse effects than COCs a depot form may delay return to fertility
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COCs and Progestins (2) Combination oral contraceptives (COCs) are effective in blocking ovulation in approximately 98% of patients and come in many different formulations Ethinyl estradiol and mestranol are commonly used estrogens Desogestrel and Norgestimate are commonly used progestins Also used for contraception are progestin-only formulations to inhibit or delay ovulation Emergency preparations such as mifepristone (RU-486), given along with misoprostol, for medical termination of intrauterine pregnancy Marc Imhotep Cray, MD
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COCs and Progestins (3) Although COCs do have adverse effects, they are associated with benefits unrelated to contraception, such as
a reduced risk of ovarian cysts, and can ameliorate menstrual and reproductive system abnormalities acne, and hirsutism
COCs ability to induce neoplasms is controversial Doses of estrogen used in hormone replacement therapy (HRT) for treatment of postmenopausal symptoms including
vasomotor manifestations genitourinary atrophy, and osteoporosis
are substantially less than those used in oral contraceptives (OCs) Marc Imhotep Cray, MD
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COCs and Progestins (4) Contraindications to COCs Combination (estrogen/progestin) contraceptives are contraindicated in women with a history of: thromboembolic disease cerebrovascular disease migraine headaches with aura estrogen-dependent cancer impaired hepatic function or active liver disease, undiagnosed uterine bleeding, and suspected pregnancy Marc Imhotep Cray, MD
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Endometriosis (ectopic growth of endometrium) Endometriosis is characterized by presence of endometrial tissue on ovaries, fallopian tubes, and peritoneum or on more remote extrauterine sites such as bowel, rectum, kidneys, and lungs Most frequent symptoms of genital tract endometriosis include: dyspareunia dysmenorrhea low back pain menstrual irregularities, and infertility Marc Imhotep Cray, MD
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Endometriosis (2) Pathogenesis endometriosis is multifactorial essentially it involves retrograde menstruation endometrial cells implant in pelvis and create “endometrial islands” that bleed and cause local inflammation in response to cyclic hormonal stimulation Natural History Endometriosis is likely to remain problematic as long as menstruation continues Therefore, mainstay of medical therapy involves interrupting or decreasing menstruation Marc Imhotep Cray, MD
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Endometriosis (3)
Pelvis: Sites of Implantation
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.
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Endometriosis (4)
Laparoscopic Views
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Endometriosis Treatment (Danazol) Danazol is a synthetic androgen w antiprogestin activity that suppresses ovarian estrogen production by inhibiting midcycle surge of LH / FSH from pituitary Resultant relatively hypoestrogenic state leads to atrophy of ectopic endometrial lesions and pain relief Danazol is started when patient is menstruating and is continued for 6 to 9 months, depending on disease severity
During therapy, pt. is usually amenorrheic, but ovulation may still occur Patients should use nonhormonal contraception b/c use of danazol during pregnancy should be avoided (Risk Categories for Use of Drugs in Pregnancy= FDA Category X) Marc Imhotep Cray, MD
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Endometriosis Treatment (2) Adverse effects characteristic of estrogen deficiency, include
headache flushing sweating atrophic vaginitis
Androgenic side effects include
acne edema hirsutism deepening of voice weight gain
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Endometriosis Treatment (3)
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Endometriosis Treatment (4)
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Estrogen Decline In premenopausal period, ovarian secretion of estradiol (E2) (most potent form of estrogen) is major source of estrogen production
In menopause, production of estradiol diminishes as ovaries cease to function In postmenopausal period (1 year after amenorrhea) gonadotropin levels increase and ovarian hormone levels decrease secondary to ovarian failure Peripheral conversion of adrenal androstenedione to estrone (E1) (one third potency of estradiol) becomes principal source of estrogen Consequences of this estrogen (ovarian estradiol) deficiency include vasomotor symptoms genitourinary atrophy N.B. Menopause assoc. symptoms include hot flashes, vaginal atrophy, osteoporosis, and coronary artery disease osteoporosis Marc Imhotep Cray, MD
(Remember, menopause causes HAVOC: Hot flashes, Atrophy of Vagina, Osteoporosis, and Coronary artery disease)
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Pituitary & Ovarian Hormone Changes in Menopause Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014
Hormone levels ↑ and ↓ cyclically during menstrual cycle Modulation occurs by pulsatile release of gonadotropins and positive and negative feedback loops
In postmenopausal period, FSH &L H levels ↑ and ovarian hormone levels ↓ secondary to ovarian failure Endogenous estrogen is primarily of adrenal origin, and E1 to E2 ratio is reversed
Vasomotor Symptoms Chief vasomotor symptoms reported by women are described as hot flashes occur over anterior part of body, especially face, neck, and chest Usually lasting a few minutes but varying in frequency and severity Symptoms are caused by a decrease in tone of arterioles results in increased blood flow to skin subsequent increase in skin temperature
Hot flashes seem to be synchronous w increased hypothalamic release of GnRH that occurs in response to estrogen deficiency GnRH neurons are coincidentally close to hypothalamic centers that regulate temperature
Estrogen replacement therapy re-establishes feedback control of hypothalamic secretion of GnRH leading to a decreased incidence of hot flashes Marc Imhotep Cray, MD
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Hot flashes
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Genitourinary Atrophy Postmenopausal estrogen deficiency leads to changes in vagina, including thinning of epithelium a ↓ blood supply dryness, and a change from acidic to a neutral or alkaline pH predisposes to infection Chief symptoms include vaginal discharge secondary to infection and painful intercourse from dryness dysuria and urinary incontinence from bladder atrophy Estrogen Tx ↑ vascularity and epithelial proliferation of vagina allows greater lubrication ↑protection from vaginitis & reduced vaginal trauma from intercourse reverses atrophy of bladder Marc Imhotep Cray, MD
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Osteoporosis and Estrogen Lower estrogen levels enhance calcium efflux from bone mineral stores ↑ serum Ca2+ levels These effects suppress PTH secretion reduces vitamin D3 synthesis ↓ intestinal calcium absorption Estrogen deficiency and advanced age also reduce secretion of hormone calcitonin inhibits bone resorption Bones thin and weaken, w ↑ risk of fractures, especially compression fractures of vertebrae (and thus height loss) and minimal-trauma hip and wrist fractures Marc Imhotep Cray, MD
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Osteoporosis and Estrogen (2) Preventive and therapeutic measures include use of estrogen, calcium, vitamin D, calcitonin, fluoride, bisphosphonates, and drugs such as raloxifene Therapeutic estrogen primarily
↓ bone resorption reduces bone loss (does not restore bone mass) ↓ calcium excretion, producing a premenopausal calcium balance ↑ vitamin D3 synthesis ↑serum calcitonin levels, and (given with calcium) decreases hip fracture occurrence
N.B. In the WHI Trial treatment of postmenopausal women with conjugated estrogen plus medroxyprogesterone (in women with a uterus) or with conjugated estrogen alone (in women without a uterus), there was improved bone density and a decreased risk of bone fractures Marc Imhotep Cray, MD
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Role of Progestins in Hormone Replacement Therapy (HRT) Unopposed estrogen is associated w a large ↑ in incidence of endometrial carcinoma is thought to be due to hormone’s continuous stimulation of endometrial hyperplasia In pts. w an intact uterus, progestin is added to estrogen therapy b/c it reduces endometrial hyperplasia by ↑ local conversion of estradiol to the less potent estrone converting endometrium from a proliferative to a secretory state, or both
Progestin also reduces risk of estrogen-induced irregular bleeding Pts. who have undergone a hysterectomy can use unopposed estrogen therapy progestin is unnecessary, especially b/c it may unfavorably alter HDL/LDL ratio Marc Imhotep Cray, MD
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Route of Hormone Administration A major pharmacologic consideration in HRT is RoA (route of administration) Oral dosage forms of estrogen go through portal circulation and thus expose liver to high hormone concentations Also, oral admin. is assoc. w more rapid conversion of estradiol to estrone Transdermal estradiol overcomes PO problem of first-pass effect and still relieves vasomotor , genitourinary symptoms and protects against bone loss
Vaginally applied estrogen cream or tablets can be used to treat genitourinary symptoms (vaginal dryness, atrophy & dyspareunia) but response may be lost after 14 days b/c of tissue cornification or down-regulation of estrogen receptors Stopping Tx for 7 to 14 days and then restarting can overcome this effect N.B Conjugated estrogen vaginal cream and its equivalents have 4 times activity of oral estrogens on local tissues 158
Estrogen or hormonal replacement therapy N.B. Current EBM data states that overall health risks from HRT in postmenopausal women appear to exceed possible benefits Mechanism of action Reduces bone resorption Uses Postmenopausal osteoporosis (reduces bone loss) Cannot restore bone Adverse effects Similar to oral contraceptives but to a lesser extent because of lower estrogen content The Women’s Health Initiative (WHI) Trial reported an increase in incidence of strokes in both estrogen-alone and the estrogen-progestin subgroups as compared with placebo groups. Thromboembolism Marc Imhotep Cray, MD
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General Adverse Effects of Estrogens Doses of estrogen used in HRT are substantially less than those used in OCs, so adverse effects of HRT tend to be less severe than those of OCs Estrogen may cause nausea, vomiting, edema, headache, hypertension, and breast tenderness
Estrogen is also a major cause of postmenopausal uterine bleeding is more likely to occur during withdrawal period if estrogen is given cyclically w progestin Progestin is likely responsible for edema and depression Androgen-like progestins can ↑ LDL/HDL ratio and cause thrombophlebitis, hirsutism, weight gain, and acne Marc Imhotep Cray, MD
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Cardiovascular and Neurologic Risks Risks and benefits of estrogen with regard to cardioprotection, neuroprotection, and carcinogenicity in postmenopausal women have been a subject of much debate Estrogen had been believed to be cardioprotective, possibly through favorable changes in lipid metabolism and direct vasodilatory effects However, the landmark trial (Women’s Health Initiative) found estrogen-progestin HRT to be associated with an increased risk of stroke, venous thromboembolism, coronary heart disease, nonfatal myocardial infarction, and death from heart disease Marc Imhotep Cray, MD
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Estrogen CV and Neurologic Risks (2) The Women’s Health Initiative (WHI) Trial also indicated that estrogen alone or w progestin did not affect progression of atherosclerotic lesions in older postmenopausal women w at least 1 coronary artery lesion Estrogen increased risk of Alzheimer disease a finding that contradicts earlier data indicating a possible association between estrogen and neuroprotection
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Diagnosis of Stroke
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Cancer Risk Estrogen was shown in Women’s Health Initiative trial and another large study to increase risk of breast cancer latter trial evaluated HRT in more than 1 million British women and found that those who received HRT (especially both estrogen and progestin) had an increased risk of development of and death resulting from breast cancer
risk of development of cancer increased w duration of HRT use, but it also declined after discontinuation of HRT
Trial indicated that estrogen-progestin reduced risk of colorectal cancer and confirmed beneficial effects on reduction of hip and vertebral fractures However, these benefits do not outweigh risks As a result in 2003, US FDA urged clinicians to limit use of HRT to a few months for temporary relief of postmenopausal symptoms Marc Imhotep Cray, MD
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Key Points Summary Hormone replacement therapy is most effective treatment option for alleviating vasomotor symptoms in postmenopausal women Risk of malignant tumors in women taking hormonal contraceptives is major concern for use of these medications in perimenopausal women Although issue is still controversial it appears that there is a small durationrelated increase in risk of breast cancer This prompted U.S. FDA to mandate addition of new safety warnings to labels of all systemic estrogens, including estrogen-only and combined estrogen−progestin products Labels caution that “use of estrogen-containing hormone therapy regimens by postmenopausal women may be associated with an increased risk of breast cancer, myocardial infarction, stroke, and thromboembolism” Marc Imhotep Cray, MD
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Hypogonadism In several conditions in females, such as Turner syndrome (ovarian dysgenesis and dwarfism), ovaries do not develop (or have no primordial follicles and may be represented only by a fibrous streak) puberty does not occur Other characteristics include: short stature primary amenorrhea sexual infantilism high gonadotropin levels, and multiple congenital abnormalities Conception is not possible Marc Imhotep Cray, MD
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Hypogonadism (2) In males, dysfunction of Leydig cells or failure of hypothalamic pituitary system can lead to inadequate secretion of androgens testosterone replacement therapy is used If testosterone deficiency occurs before puberty results in failure to complete puberty After completion of puberty testosterone defic. can lead to o loss of libido and energy o decreased muscle mass and strength o decreased hematocrit and hemoglobin, and o decreased bone mineral density Marc Imhotep Cray, MD
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Hypogonadism examples Klinefelter syndrome [male] (47,XXY) Dysgenesis of seminiferous tubules↓ inhibin B↑ FSH Abnormal Leydig cell function ↓testosterone ↑LH ↑ estrogen Testicular atrophy, eunuchoid body shape, tall, long extremities, gynecomastia, female hair distribution A May present with developmental delay Presence of inactivated X chromosome (Barr body) Common cause of hypogonadism seen in infertility work-up Turner syndrome [female] (45,XO) Menopause before menarche ↓estrogen leads to ↑LH, FSH Short stature (if untreated), ovarian dysgenesis (streak ovary), shield chest, bicuspid aortic valve, coarctation (femoral < brachial pulse), lymphatic defects (result in webbed neck or lymphedema in feet, hands), horseshoe kidney Most common cause of 1° amenorrhea Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014
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Hypogonadism Treatment & Adverse Effects For females, appropriate therapy with estrogen, usually w progestin, replicates most events of puberty
Genital structures grow to normal size, breasts develop, axillary and pubic hair grows, and body achieves a normal FM contour
Estrogen may increase growth, but if used too soon, it can accelerate epiphyseal fusion cause a short final height (treated w androgens and growth hormone)
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Hypogonadism Tx & Adverse Effects (2) For male testosterone deficiency, an oral drug is ineffective b/c of liver metabolism Intramuscular testosterone (cypionate or enanthate) or transdermal testosterone overcomes first-pass metabolism to reach normal serum concentrations Adverse effects In prepubertal children testosterone causes acne, hirsutism, gynecomastia, and sexual aggression and growth disturbances Excess androgen in men can cause priapism or impotence, reduced spermatogenesis, and gynecomastia Androgens can also cause edema and increased LDL/HDL ratio may be harmful to those with CHF or hyperlipidemia, respectively Marc Imhotep Cray, MD
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THE END
See next slide for further study. Marc Imhotep Cray, MD
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Companion Tools and Resources (online) eNotes Endocrine and Reproductive System Pharmacology (NB: The reproductive section is companion to this presentation.) MedPharm Guidebook Unit 8 Drugs Used In Disorders of Reproductive System Case-based Learning Cases 40, 45, 51, 54 eLearning (cloud folders) M and FM Reproductive System & FM Breast Pregnancy, Childbirth, & the Puerperium Marc Imhotep Cray, MD
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