Antiestrogénios

Classificação

Devem ser consideradas várias classes principais de antiestrogénios. Os fármacos protótipos em cada classe estão assinalados com um asterisco (*).

• Moduladores seletivos do recetor de estrogénio ( SERMs SERMs A structurally diverse group of compounds distinguished from estrogens by their ability to bind and activate estrogen receptors but act as either an agonist or antagonist depending on the tissue type and hormonal milieu. They are classified as either first generation because they demonstrate estrogen agonist properties in the endometrium or second generation based on their patterns of tissue specificity. Antiestrogens):
  • Atividade antagonista (isto é, antiestrogénica) em alguns tecidos e atividade agonista (isto é, estrogénica) noutros tecidos
  • Agentes:
    • Tamoxifeno*
    • Raloxifeno
    • Ospemifeno
    • Bazedoxifeno
    • Citrato de clomifeno
• Reguladores negativos seletivos do recetor de estrogénio ( SERDs SERDs Antiestrogens):
  • Também conhecidos como antagonistas puros de estrogénios
  • Só têm atividade antagonista
  • Agentes:
    • Fulvestrant Fulvestrant An estradiol derivative and estrogen receptor antagonist that is used for the treatment of estrogen receptor-positive, locally advanced or metastatic breast cancer. Antiestrogens* (o único composto aprovado pela FDA)
    • Estão a ser desenvolvidos e/ou a passar por ensaios clínicos vários compostos adicionais.
• Inibidores da aromatase Aromatase An enzyme that catalyzes the desaturation (aromatization) of the ring a of C19 androgens and converts them to C18 estrogens. In this process, the 19-methyl is removed. This enzyme is membrane-bound, located in the endoplasmic reticulum of estrogen-producing cells of ovaries, placenta, testes, adipose, and brain tissues. Aromatase is encoded by the cyp19 gene, and functions in complex with NADPH-ferrihemoprotein reductase in the cytochrome p450 system. Adipose Tissue: Histology:
  • Anastrozol*
  • Letrozol
  • Exemestano
• Outros:
  • Análogos da hormona libertadora de gonadotrofinas (GnRH, pela sigla em inglês):
    • Leuprolida
    • Ganirelix Ganirelix Antiestrogens
    • Elagolix Elagolix Antiestrogens
  • Androgénios: Danazol Danazol A synthetic steroid with antigonadotropic and anti-estrogenic activities that acts as an anterior pituitary suppressant by inhibiting the pituitary output of gonadotropins. It possesses some androgenic properties. Danazol has been used in the treatment of endometriosis and some benign breast disorders. Antiestrogens
  • Progestinas

Moduladores Seletivos do Recetor de Estrogénio e Reguladores Seletivos do Recetor de Estrogénio

Mecanismo de ação dos SERMs SERMs A structurally diverse group of compounds distinguished from estrogens by their ability to bind and activate estrogen receptors but act as either an agonist or antagonist depending on the tissue type and hormonal milieu. They are classified as either first generation because they demonstrate estrogen agonist properties in the endometrium or second generation based on their patterns of tissue specificity. Antiestrogens

Tamoxifeno, raloxifeno, ospemifeno, bazedoxifeno e citrato de clomifeno:

• Ligam-se competitivamente aos receptores de estrogénio (REs)
• Atividade agonista e antagonista, dependendo do tecido alvo:
  • Atividade antiestrogénica na mama
  • Tendem a ter atividade estrogénica (ou seja, agonista) no:
    • Útero
    • Ossos
    • Fígado
• Recetores de estrogénio:
  • Localizados no núcleo (e não na membrana celular)
  • Atuam como fator de transcrição dependente de ligante (quando o estrogénio é o ligante necessário para a ligação ao DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure)
  • Quando o estrogénio se liga ao RE, o complexo ER-estrogénio liga-se aos elementos de resposta do estrogénio (EREs, pela sigla em inglês) na região promotora dos genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure alvo.
  • A ligação ao ERE pode ativar ou reprimir a expressão do gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics alvo.
• Como os efeitos do SERM diferem entre os tecidos não é totalmente compreendido.
• Teoria: O complexo SERM-RE interage com diferentes cofatores presentes em diferentes tecidos.

Mecanismo de ação dos SERDs SERDs Antiestrogens

Fulvestranto:

• Antagonista competitivo de alta afinidade que impede a ligação do estrogénio ao RE
• Semelhante ao ligante de estrogénio endógeno → compete com o estrogénio pela ligação ao domínio de ligação do RE
• Pura atividade antagonista dos RE sem atividade agonista
• Produz um complexo dentro do núcleo da célula (localização do RE), que causa a regulação negativa dos recetores de estrogénio
• Efeito dose-dependentes (e.g., maior dose de fulvestrant Fulvestrant An estradiol derivative and estrogen receptor antagonist that is used for the treatment of estrogen receptor-positive, locally advanced or metastatic breast cancer. Antiestrogens → mais MAIS Androgen Insensitivity Syndrome regulação negativa)
• Sem estimulação estrogénica → o crescimento do tumor Tumor Inflammation hormonodependente é inibido

Efeitos fisiológicos

Os SERMs SERMs A structurally diverse group of compounds distinguished from estrogens by their ability to bind and activate estrogen receptors but act as either an agonist or antagonist depending on the tissue type and hormonal milieu. They are classified as either first generation because they demonstrate estrogen agonist properties in the endometrium or second generation based on their patterns of tissue specificity. Antiestrogens atuam como agonistas do estrogénio em alguns tecidos e antagonistas do estrogénio noutros.

Efeitos fisiológicos dos SERDs SERDs Antiestrogens:

O fulvestrant Fulvestrant An estradiol derivative and estrogen receptor antagonist that is used for the treatment of estrogen receptor-positive, locally advanced or metastatic breast cancer. Antiestrogens possui efeitos puramente antiestrogénicos nos tecidos. Os principais efeitos fisiológicos incluem:

• ↓ Estimulação estrogénica para a mama
• ↓ Densidade mineral óssea (DMO)
• Supressão do crescimento endometrial

Farmacocinética

• Absorção:
  • Rapidamente absorvido quando tomado por via oral
  • A maioria tem baixa biodisponibilidade (< 10%)
• Distribuição:
  • Amplamente distribuído
  • Altamente ligado a proteínas (principalmente à albumina, não à globulina de ligação das hormonas sexuais)
• Metabolismo:
  • Metabolismo hepático
  • Tamoxifeno: via CYP2D6 e CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers)/CYP3A5 para metabolitos ativos mais MAIS Androgen Insensitivity Syndrome potentes
  • Raloxifeno: sofre extenso metabolismo de 1ª passagem e transforma-se em conjugados de glicuronídeos
  • Bazedoxifeno: metabolismo hepático (não via enzimas CYP)
  • Ospemifeno: via CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers), CYP2C9 CYP2C9 A cytochrome p-450 subtype that has specificity for acidic xenobiotics. It oxidizes a broad range of important clinical drugs that fall under the categories of nonsteroidal anti-inflammatory agents; hypoglycemic agents; anticoagulants; and diuretics. Anticoagulants e CYP2C19
  • Fulvestrant Fulvestrant An estradiol derivative and estrogen receptor antagonist that is used for the treatment of estrogen receptor-positive, locally advanced or metastatic breast cancer. Antiestrogens: via CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) para metabolitos ativos
• Excreção:
  • Principalmente fecal
  • Semi-vida: geralmente longa:
    • Tamoxifeno: 5-7 dias
    • Raloxifeno e bazedoxifeno: aproximadamente 30 horas
    • Fulvestrant Fulvestrant An estradiol derivative and estrogen receptor antagonist that is used for the treatment of estrogen receptor-positive, locally advanced or metastatic breast cancer. Antiestrogens: aproximadamente 40 dias

Indicações

As indicações primárias para cada medicamento são indicadas com um asterisco (*):

• Cancro da mama e outros problemas de mama:
  • Agentes:
    • Tamoxifeno*
    • Raloxifeno
    • Fulvestranto*
  • Tratamento adjuvante no cancro da mama
  • Carcinoma ductal in situ (CDIS)
  • Redução profilática do risco em indivíduos de alto risco
  • Ginecomastia (crescimento mamário em homens)
  • Mastalgia severa (dor no peito)
• Prevenção e tratamento da osteoporose pós-menopausa:
  • Raloxifeno*
  • Bazedoxifeno*
• Outros sintomas da menopausa:
  • Bazedoxifeno: sintomas vasomotores* (e.g., ondas de calor Calor Inflammation, suores noturnos)
  • Ospemifeno: secura vaginal*
• Infertilidade:
  • Clomifeno: para indução da ovulação*
  • Tamoxifeno:
    • Para indução da ovulação em indivíduos com cancro da mama
    • Para a infertilidade perante fator masculino idiopático
• Puberdade precoce (e.g.o, síndrome de McCune-Albright):
  • Tratamento de 1ª linha: inibidores da aromatase Aromatase An enzyme that catalyzes the desaturation (aromatization) of the ring a of C19 androgens and converts them to C18 estrogens. In this process, the 19-methyl is removed. This enzyme is membrane-bound, located in the endoplasmic reticulum of estrogen-producing cells of ovaries, placenta, testes, adipose, and brain tissues. Aromatase is encoded by the cyp19 gene, and functions in complex with NADPH-ferrihemoprotein reductase in the cytochrome p450 system. Adipose Tissue: Histology
  • Agentes de 2ª linha:
    • Tamoxifeno
    • Fulvestrant Fulvestrant An estradiol derivative and estrogen receptor antagonist that is used for the treatment of estrogen receptor-positive, locally advanced or metastatic breast cancer. Antiestrogens

Efeitos adversos

• Ondas de calor Calor Inflammation (comuns com todos os SERMs SERMs A structurally diverse group of compounds distinguished from estrogens by their ability to bind and activate estrogen receptors but act as either an agonist or antagonist depending on the tissue type and hormonal milieu. They are classified as either first generation because they demonstrate estrogen agonist properties in the endometrium or second generation based on their patterns of tissue specificity. Antiestrogens e SERDs SERDs Antiestrogens)
• Tromboembolismo venoso (TEV) (uma preocupação com todos os agentes):
  • Trombose venosa profunda
  • Embolia pulmonar
• Neoplasias e lesões uterinas (tamoxifeno, ospemifeno, clomifeno):
  • Carcinoma endometrial
  • Carcinoma uterino (sarcoma)
  • Pólipos endometriais
  • Hiperplasia endometrial
  • Miomas uterinos
• Efeitos oculares (tamoxifeno)
• Outros efeitos colaterais comuns (todos os agentes):
  • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Tonturas
  • Distúrbios GI
  • Espasmos musculares
  • Artralgias/dor óssea

Contraindicações

• Hipersensibilidade
• História ou TEV atual
• Gravidez
• Hemorragia vaginal inexplicável
• Terapêutica concomitante com varfarina (tamoxifeno)
• Usar com cautela na insuficiência hepática.

Inibidores de Aromatase

Descrição Geral

Os inibidores de aromatase Aromatase An enzyme that catalyzes the desaturation (aromatization) of the ring a of C19 androgens and converts them to C18 estrogens. In this process, the 19-methyl is removed. This enzyme is membrane-bound, located in the endoplasmic reticulum of estrogen-producing cells of ovaries, placenta, testes, adipose, and brain tissues. Aromatase is encoded by the cyp19 gene, and functions in complex with NADPH-ferrihemoprotein reductase in the cytochrome p450 system. Adipose Tissue: Histology impedem a conversão de testosterona em estrogénio, que é um processo conhecido como aromatização. Os fármacos da classe incluem o anastrozol, o letrozol e o exemestano. Estes fármacos são mais MAIS Androgen Insensitivity Syndrome frequentemente usados no tratamento do cancro da mama na pós-menopausa.

Mecanismo de ação

• Os inibidores da aromatase Aromatase An enzyme that catalyzes the desaturation (aromatization) of the ring a of C19 androgens and converts them to C18 estrogens. In this process, the 19-methyl is removed. This enzyme is membrane-bound, located in the endoplasmic reticulum of estrogen-producing cells of ovaries, placenta, testes, adipose, and brain tissues. Aromatase is encoded by the cyp19 gene, and functions in complex with NADPH-ferrihemoprotein reductase in the cytochrome p450 system. Adipose Tissue: Histology inibem a ação da aromatase Aromatase An enzyme that catalyzes the desaturation (aromatization) of the ring a of C19 androgens and converts them to C18 estrogens. In this process, the 19-methyl is removed. This enzyme is membrane-bound, located in the endoplasmic reticulum of estrogen-producing cells of ovaries, placenta, testes, adipose, and brain tissues. Aromatase is encoded by the cyp19 gene, and functions in complex with NADPH-ferrihemoprotein reductase in the cytochrome p450 system. Adipose Tissue: Histology:
  • Anastrozol e letrozol: ligam-se reversivelmente à aromatase Aromatase An enzyme that catalyzes the desaturation (aromatization) of the ring a of C19 androgens and converts them to C18 estrogens. In this process, the 19-methyl is removed. This enzyme is membrane-bound, located in the endoplasmic reticulum of estrogen-producing cells of ovaries, placenta, testes, adipose, and brain tissues. Aromatase is encoded by the cyp19 gene, and functions in complex with NADPH-ferrihemoprotein reductase in the cytochrome p450 system. Adipose Tissue: Histology
  • Exemestano: liga-se irreversivelmente à aromatase Aromatase An enzyme that catalyzes the desaturation (aromatization) of the ring a of C19 androgens and converts them to C18 estrogens. In this process, the 19-methyl is removed. This enzyme is membrane-bound, located in the endoplasmic reticulum of estrogen-producing cells of ovaries, placenta, testes, adipose, and brain tissues. Aromatase is encoded by the cyp19 gene, and functions in complex with NADPH-ferrihemoprotein reductase in the cytochrome p450 system. Adipose Tissue: Histology
• Leva a ↓ níveis de estrogénio em mulheres na pós-menopausa:
  • O estrogénio estimula o crescimento tumoral em muitos cancros da mama.
  • Efeito geral dos inibidores da aromatase Aromatase An enzyme that catalyzes the desaturation (aromatization) of the ring a of C19 androgens and converts them to C18 estrogens. In this process, the 19-methyl is removed. This enzyme is membrane-bound, located in the endoplasmic reticulum of estrogen-producing cells of ovaries, placenta, testes, adipose, and brain tissues. Aromatase is encoded by the cyp19 gene, and functions in complex with NADPH-ferrihemoprotein reductase in the cytochrome p450 system. Adipose Tissue: Histology:
    • Diminuir a massa tumoral
    • Atrasar a progressão de tumores responsivos a hormonas
• Aromatase Aromatase An enzyme that catalyzes the desaturation (aromatization) of the ring a of C19 androgens and converts them to C18 estrogens. In this process, the 19-methyl is removed. This enzyme is membrane-bound, located in the endoplasmic reticulum of estrogen-producing cells of ovaries, placenta, testes, adipose, and brain tissues. Aromatase is encoded by the cyp19 gene, and functions in complex with NADPH-ferrihemoprotein reductase in the cytochrome p450 system. Adipose Tissue: Histology:
  • Enzima chave necessária na síntese de estrogénio
  • Converte andrógenos em estrogénios:
    • Bloqueia a testosterona → estradiol Estradiol The 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. Noncontraceptive Estrogen and Progestins
    • Bloqueia a androstenediona → estrona
  • Localizada dentro de:
    • Células da granulosa nos ovários (principal local de produção de estrogénio em mulheres na pré-menopausa)
    • Mama
    • Tecido adiposo
    • Glândulas suprarrenais
    • Cérebro
    • Osso
• Porque é que os inibidores de aromatase Aromatase An enzyme that catalyzes the desaturation (aromatization) of the ring a of C19 androgens and converts them to C18 estrogens. In this process, the 19-methyl is removed. This enzyme is membrane-bound, located in the endoplasmic reticulum of estrogen-producing cells of ovaries, placenta, testes, adipose, and brain tissues. Aromatase is encoded by the cyp19 gene, and functions in complex with NADPH-ferrihemoprotein reductase in the cytochrome p450 system. Adipose Tissue: Histology são usados em mulheres na pós-menopausa:
  • Antes da menopausa, o eixo hipotálamo-hipófise-ovariano (HPO, pela sigla em einglês) é funcional e responsivo.
  • Inibem a produção de estrogénio gonadal → ↓ estrogénio circulante → menor inibição da:
    • GnRH
    • Hormona folículo estimulante ( FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle, pela sigla em inglês)
    • Hormona luteinizante ( LH LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle, pela sigla em inglês)
  • Menor inibição da GnRH, FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle e LH LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle → ↑ GnRH, FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle e LH LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle → estimula os ovários a ↑ produção de androgénios
  • O eixo HPO “desliga-se” na menopausa, com a cessação da função ovárica.
  • Alguns locais extragonadais continuam a produzir estrogénio capaz de estimular o cancro de mama em mulheres na pós-menopausa → os inibidores da aromatase Aromatase An enzyme that catalyzes the desaturation (aromatization) of the ring a of C19 androgens and converts them to C18 estrogens. In this process, the 19-methyl is removed. This enzyme is membrane-bound, located in the endoplasmic reticulum of estrogen-producing cells of ovaries, placenta, testes, adipose, and brain tissues. Aromatase is encoded by the cyp19 gene, and functions in complex with NADPH-ferrihemoprotein reductase in the cytochrome p450 system. Adipose Tissue: Histology inibem a produção de estrogénio

Farmacocinética

Anastrozol, Letrozol:

• Absorção (ambos):
  • Bem absorvidos por via oral
  • Absorção rápida
  • A extensão da absorção não é afetada pelos alimentos.
• Ligação a proteínas (ambos): fraca a moderada
• Metabolismo:
  • Metabolismo hepático em metabolitos inativos
  • Anastrozol: via N-desalquilação, hidroxilação e glucuronidação
  • Letrozol: via CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) e CYP2A6
• Excreção (ambos):
  • Principalmente fecal (10% de urina)
  • Semi-vida: aproximadamente 2 dias

Exemestano:

• Absorção:
  • Moderadamente bem absorvido após administração oral
  • ↑ Pós-prandial
• Distribuição:
  • Amplamente distribuído nos tecidos
  • 90% está ligado a proteínas (principalmente à albumina e à glicoproteína 𝛂₁-ácida)
• Metabolismo:
  • Extenso metabolismo hepático em metabolitos inativos
  • Via oxidação CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) e redução do grupo 17-ceto
• Excreção:
  • Praticamente dividido entre a urina (principalmente como metabolitos) e as fezes
  • Semi-vida: aproximadamente 24 horas

Indicações

• Cancro da mama avançado em mulheres na pós-menopausa
• Redução do risco de cancro da mama em mulheres na pós-menopausa
• Uso off-label em carcinomas ováricos e uterinos recorrentes
• Indicações adicionais do letrozol:
  • Infertilidade: agente de 1ª linha para indução da ovulação em mulheres anovulatórias com síndrome do ovário poliquístico (SOP)
  • Puberdade precoce periférica (e.g., síndrome de McCune-Albright)

Efeitos adversos

• Sensações súbitas de calor Calor Inflammation
• Disfunção sexual (normalmente devido a vaginite atrófica)
• Osteoporose/ osteopenia Osteopenia Osteoporosis: ↓ DMO e ↑ risco de fratura
• Efeitos músculo-esqueléticos:
  • Artralgia/dor óssea
  • Rigidez articular
  • Mialgias
  • Síndrome do túnel cárpico
• Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema periférico
• Dificuldades gastrointestinais:
  • Náuseas/vómitos
  • Diarreia/obstipação
  • Dor abdominal
• Aumento de peso
• Hipercolesterolemia
• Eventos cardiovasculares isquémicos (os estudos são mistos):
  • Provável ↑ risco em indivíduos com doença cardiovascular preexistente
  • ↑ Risco comparado com o tamoxifeno (provavelmente não é um grande ↑ risco comparado com um placebo Placebo Any dummy medication or treatment. Although placebos originally were medicinal preparations having no specific pharmacological activity against a targeted condition, the concept has been extended to include treatments or procedures, especially those administered to control groups in clinical trials in order to provide baseline measurements for the experimental protocol. Epidemiological Studies)
  • Os eventos podem incluir:
    • Angina de peito
    • Enfarte agudo do miocárdio
    • AVC isquémico

Contraindicações

• Hipersensibilidade
• Gravidez
• Amamentação
• Status pré-menopausa em uso para tratamento de cancro da mama

Análogos da Hormona Libertadora de Gonadotrofina

Descrição Geral

• A GnRH é um componente chave do eixo HPO:
  • O hipotálamo liberta GnRH.
  • A GnRH estimula a libertação de FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle e LH LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle da hipófise anterior.
  • A FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle e LH LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle estimulam o ovário, que produz estrogénio e progesterona.
• A GnRH é libertado de forma pulsátil do hipotálamo.
• Os análogos de GnRH ligam-se aos recetores de GnRH na hipófise.
• Tanto os agonistas quanto os antagonistas suprimem a libertação de FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle e LH LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle, levando à supressão de:
  • Desenvolvimento do folículo
  • Ovulação
  • Produção de estrogénio e progesterona
• Não deve ser usado como contraceção
• Os efeitos adversos são semelhantes a outros antiestrogénios:
  • Sensações súbitas de calor Calor Inflammation
  • Suores noturnos
  • Alterações do humor Humor Defense Mechanisms
  • Secura vaginal
  • Perda óssea (o tratamento geralmente é limitado a < 6 meses)

Agonistas de GnRH

Leuprolida:

• A exposição contínua (em vez da exposição pulsátil) ao GnRH suprime a FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle e a LH LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle → ↓ desenvolvimento folicular → ↓ estrogénio
• Cria uma “menopausa médica” reversível até que os efeitos desapareçam
• A supressão leva alguns dias → os indivíduos geralmente experimentam “crises” de sintomas antes da melhoria
• Dada como injeções IM a cada 1–3 meses
• Indicações:
  • Puberdade precoce central
  • Tratamento de curto prazo (< 6 meses) de miomas uterinos:
    • Reduzir o tamanho do mioma antes da cirurgia
    • Interromper a hemorragia menstrual intensa dando tempo para a correção da anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types antes da cirurgia
    • Suprimir os sintomas até que a menopausa natural ocorra em mulheres na perimenopausa
  • Tratamento de curto prazo (< 6 meses) da endometriose (e.g., para “queimar” os implantes antes de iniciar contracetivos hormonais como tratamento de longo prazo)
  • Tratamento do cancro da próstata avançado

Antagonistas de GnRH

Ganirelix Ganirelix Antiestrogens, Elagolix Elagolix Antiestrogens:

• Bloqueam competitivamente os recetores de GnRH na hipófise
• Suprimem a libertação de FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle e LH LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle para evitar a ovulação
• Não têm o “flare” associado aos agonistas de GnRH
• Indicações:
  • Ganirelix Ganirelix Antiestrogens: Usado como parte de tratamentos de fertilidade durante ciclos ovulatórios controlados (são administrados outros fármacos para desenvolver folículos e desencadear a ovulação)
  • Elagolix Elagolix Antiestrogens:
    • Endometriose
    • Dispareunia (coito doloroso)

Androgénios e Progestinas

• Os androgénios e progestinas sintéticas (estruturalmente semelhantes aos androgénios) opõem-se ao estrogénio no tecido endometrial.
• Suprimem o crescimento endometrial → causam um afinamento do tecido endometrial
• Devido aos efeitos colaterais androgénicos, os androgénios raramente são usados para tratamento em mulheres.
• As progestinas são um componente primário da maioria dos contracetivos hormonais.
• Indicações:
  • Contraceção
  • Condições que melhoram quando o crescimento endometrial é suprimido:
    • Endometriose
    • Dismenorreia
    • Hemorragia menstrual intensa
    • Hiperplasia endometrial

Comparação de Fármacos