Medicamentos atuantes no sistema reprodutivo feminino Dúvidas denucci@gdenucci.com Arquivo Medicamentos atuantes no sistema reprodutivo feminino Site www.gdenucci.com

The anatomy of the female internal genitalia and accessory sex organs Walter F. Boron/ Emile L. Boulpaep – Medical Physiology – Fig 54-1

The anatomy of the female internal genitalia and accessory sex organs Walter F. Boron/ Emile L. Boulpaep – Medical Physiology – Fig 54-1

Ovarian cycle Rupture of mature follice and release of ovum (ovulatory phase) Growth and development of the follice (follicular phase) Corpus luteum formation (luteal phase) Corpus luteum degeneration Foyes Principles of Medicinal Chemistry – Fig. 29.2

Correlation of serum gonadotrophic and ovarian hormone levels and feedback mechanisms FSH-LH (pulses/hr) Follicular phase Hypothalamus GnRH (pulses /hr) Pituitary LH-FSH Ovary Estrogen Progesterone FSH Estrogen 50 40 30 20 10 500 400 300 200 100 10 9 8 7 6 5 4 3 2 1 Serum levels Menses LH Progesterone 2 4 6 8 10 12 14 16 18 20 22 24 26 28 ng ml pg ml mlU ml Days

Combined oral contraceptives (COs; all doses in µg except where noted) Agent Estrogen Progestogen Pharmacological features Monophasic Continuous administration may be extended up to 12 weeks to minimize inconvinience/symptoms of breakthrough Available in 21- or 28 day dose packs ME 50 NE 1 mg EE 50 NE 1 mg EE 50 NG 500 EE 35 NE 1 mg EE 35 NE 500 EE 35 NE 400 EE 35 LNG 150 EE35 LNG 100 EE 30 DRG 150 Less androgenic effects EE 30 NG 300 Less androgenic effects EE 30 LNG 150 EE 20 LNG 100 Less nausea and bloating Increase breakthrough bleeding Integrated Pharmacology – Fig 15.47

Combined oral contraceptives (COs; all doses in µg except where noted) Agent Estrogen Progestogen Pharmacological features Multiphasic Reduced overall progestogen dose minimizes weight gain, fluid retention, dysmenorrhea EE 30, 40, 30 LNG 50, 75, 125 EE 35 MGM 180, 215, 250 Less androgenic effects EE 35 NE 50, 100, 50 EE 35 NE 0.5, 0.75, 1 mg EE 35 NE 0.5, 1 mg Low Dose Minimizes headache, menorrhagia EE 20 NE 1 mg EE 20, 0 , 10 DEG 150 Less androgenic effects Antiandrogenic EE 50 CYP 2 mg Reduces androgenic effects in polycystic ovary syndrome (not registered in US) Integrated Pharmacology – Fig 15.47

Estrogens excreted in urine Estrogen secretion throughout the sexual life of the female human being 400 300 200 100 Puberty Menopause Estrogens excreted in urine (µg/24 hr) 0-----12 13------40 50 60 Age (yr) Guyton & Hall – Textbook of Medical Physiology – fig 81.10

Walter F. Boron/ Emile L. Boulpaep – Medical Physiology – Fig 54-1

Hormônios na menopausa Secreção de GnRH aumentada (tanto frequência como amplitude) Aumento dos níveis de FSH e LH (até 4x) Diminuição dos níveis de estradiol (< 20 pg/mL)  

Sintomas da Menopausa Ondas de calor (60-82%) Calafrios Ansiedade

Falência ovariana prematura Amenorréia por 6 meses <40 anos FSH > 40 IU/mL

Effect of SERMs on estrogen tissues Integrated Pharmacology – fig 20.8

Osteoporose Deterioração da microarquitetura do esqueleto causando aumento da fragilidade dos ossos

Bone mass wich age Integrated Pharmacology – fig 20.2

Densitometria Mulheres acima de 65 anos Mulheres menopausadas que apresentaram fratura Candidatas a tratamento de osteoporose Mulheres utilizando reposição hormonal Mulheres menopausadas abaixo de 65 anos mas que apresentam fatores de risco para osteoporose

Prevenção farmacológica Suplementação de cálcio - 1200mg/dia Vitamina D - 400-800 IU/dia

Approximate body stores of vitamins Vitamin Body’s storage capacity Vitamina B12 3-6years Vitamina A 6-10 months Vitamina D 2-4 months Folic acid 1-3 months Vitamin C 2-4 weeks Vitamin B3 2-4 weeks Vitamin K 1-2 weeks Vitamin B1 1-2 weeks Vitamin B2 1-2 weeks Vitamin B6 1-2 weeks Integrated Pharmacology – fig 27.6

Mode of action of vitamins Co-enzymes Antioxidants Hormones Vitamin B1 Vitamin C Vitamin A Vitamin B2 Vitamin E Vitamin D Vitamin B3 Vitamin B6 Vitamina B12 Vitamin K Biotin Folic acid Pantothenic acid Integrated Pharmacology – fig 27.7

Approximate body stores of vitamins Vitamin Body’s storage capacity Vitamina A 5000 IU Vitamin B1 1.5 mg Vitamin B2 1.7 mg Vitamin B3 20 mg Vitamin B6 2 mg Vitamina B12 0.003 mg Vitamin C 60 mg Vitamina D 400 IU Vitamin E 30 IU Vitamin K 0.08 mg Pantothenic acid 10 mg Biotin 0.3 mg Folic acid 0.4 mg Integrated Pharmacology – fig 27.9

Therapy for osteoporosis Medication Type Dose Indications Alendronate Bisphosphonate 10 mg qd Prevention and treatment Calcitonin Salmon calcitonin 200 IU/ spray qd Treatment hPTH(1-34) Parathyroid hormone 400 U Treatment Raloxifene SERM 60 mg qd Prevention and treatment Residronate Bisphosphonate 5 mg qd Prevention and treatment Tibolone Synthetic steroid 2.5 mg qd Prevention (not FDA approved) Essential of Reproductive Medicine – Tab. 28-2

Correlation of serum gonadotrophic and ovarian hormone levels and feedback mechanisms FSH-LH (pulses/hr) Follicular phase Hypothalamus GnRH (pulses /hr) Pituitary LH-FSH Ovary Estrogen Progesterone FSH Estrogen 50 40 30 20 10 500 400 300 200 100 10 9 8 7 6 5 4 3 2 1 Serum levels Menses LH Progesterone 2 4 6 8 10 12 14 16 18 20 22 24 26 28 ng ml pg ml mlU ml Days

Serum levels of estrogens, pro-gestins, and hCG in women during the first trimester of pregnancy Essential Reproductive Medicine – Fig 6-2

Gonadotrofina coriônica humana (hCG) Produzido pelo embrião logo após a fertilização Previne a desintegração do corpo lúteo Mantem a produção de progesterona Utilizado como marcador de gravidez Indutor de ovulação

P E2 E1, E2 and E3, ng/ml E3 E1 Weeks of Gestation Serum levels of estrone (E1) estradiol (E2), estriol (E3), and progesterone (P) in women during the second and third trimester of normal pregnancy 180 120 60 P 24 16 8 E2 E3 E1, E2 and E3, ng/ml E1 0 10 20 30 40 Weeks of Gestation Essential Reproductive Medicine – Fig 6-3

Conjugated and esterified estrogens HO Equilin Equilin sodium sulfate R = H R = SO3 –Na+ O Estrone Estrone sodium sulfate Piperazine estrone sulfate R = H R = SO3 –Na+ R = SO3 + N NH H RO H Foyes Principles of Medicinal Chemistry – fig. 29.7

http://www.eset.com – Clinical Endocrinology & Metabolism

Disfunção Ovulatória I - hipofunção hipotalâmica-hipofisária II - Disregulação hipotalâmica-hipofisária-ovariana (ovário policístico) III - falência ovariana prematura

Hipofunção hipotalâmica-hipofisária (prolactina aumentada) Agonistas de dopamina Clomifen/gonadotrofinas

Disfunção hipotalâmica-hipofisária II Citrato de clomifeno Gonadotrofinas contendo FSH Com pico precoce de LH em cada ciclo: Agonista de GnRH Antagonista de GnRH Com resistência a insulina Metformina Com hiperandrogenismo Glicocorticóides (prednisona ou dexametasona)

Citrato de clomifeno Agonista/antagonista dos receptores de estrógeno no hipotálamo/hipófise Inibe o feedback negativo dos estrógenos Estimula a liberação de gonadotrofinas Promove crescimento folicular Promove aumento da frequência de pulso de LH

Clomifeno - contra-indicações Cistos ovarianos Gravidez Doença hepática Problemas visuais (2%) Outros eventos adversos: ondas de calor

Agonista de Dopamina Bromocriptina (Parlodel) Inibe a liberação de prolactina (receptores D1/D2)

The hypothalamic-Pituitary-Ovarian Axis and the Role of Insulin

Glicocorticóides Bloqueia a liberação de andrógenos (abole pico circadiano de ACTH) Atua tanto na adrenal como no ovário Prednisona/Dexametasona

Gonadotrofinas Purificadas de urina Utilizado na falha de clomifeno

Gonadotrofinas Menotrofinas Urofolitrofinas Preparações purificadas de FSH FSH/LH recombinante

Gonadotrofina coriônica humana (hCG) Produzido pelo embrião logo após a fertilização Previne a desintegração do corpo lúteo Mantem a produção de progesterona Utilizado como marcador de gravidez Indutor de ovulação

Presença e proliferação de tecido endometrial fora do útero Endometriose Presença e proliferação de tecido endometrial fora do útero

The anatomy of the female internal genitalia and accessory sex organs Walter F. Boron/ Emile L. Boulpaep – Medical Physiology – Fig 54-1

Endometriose Mais frequente no ovário Ligamento útero-sacro Parede pélvica Fundo de saco posterior

Endometriose Dismenorréia Dispaurenia Infertilidade

Endometriose Doença dependente de estrógeno Raro portanto na menopausa

Endometriose ACO monofásico baixa dose Danazol - teratogênico Progestágenos Agonistas de GnRH com terapia de reposição

Drug Summary Table – Pharmacology of Reproduction Gonadotropin-Releasing Hormone (GnRH) Agonists Drug Gonadorelin Gorserelin Histrelin Leuprolide Nafarelin Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454

GnRH agonistas/antagonistas para endometriose Generic name Brand name Form Dosage Buserelin Suprecur Nasal spray Buserelin comes in a nasal spray pump. The recommended dosage is two sprays into each nostril every 8 hours (3 times a day). Suprefact injectable Daily injection Daily injections of buserelin start with a dosage of 200 micrograms, and increase up to a maximum of 500 micrograms. The final dose is the minimum needed to alleviate pain symptoms. Goserelin Zoladex Monthly or three-monthly injection Goserelin is embedded in a small biodegradable implant about the size of a grain of rice. The implant is injected under the skin in the lower half of the abdomen once a month. Leuprorelin Leuprolide Lupron Depot Monthly injection Leuprorelin comes as a monthly or, three-monthly, injection that is injected under the skin of the abdomen or arm, or sometimes into the buttock or thigh muscles. Prostap SR Enantone Lucrin Depot Trenantone-Gyn Three-monthly injection Naferelin Synarel Nafarelin comes in a nasal spray pump. The recommended dosage is one spray of the pump into one nostril in the morning, and one spray into the other nostril in the evening every day. In a few women, the recommended dosage does not stop menstruation. If symptoms persist in these women, the dosage may be increased to one spray in both nostrils morning and night. Synarella Triptorelin Decapeptyl SR Monthly and three monthly injection Triptorelin comes as an injection that is injected under the skin or into the buttock muscle once a month or once every three months. Gonapeptyl http://www.eset.com - GnRH-agonists as a treatment for endometriosis - by Ros Wood (Australia)