Antiestrogens

Antiestrogens are medications decreasing the estrogenic effects in the body. The antiestrogens include selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), aromatase inhibitors, and several others, which include medications suppressing the gonadotropins or counteracting the effects of estrogen. Antiestrogens are most commonly used in the treatment of breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer but also treat precocious puberty Precocious puberty Precocious puberty (PP) is the appearance of secondary sexual characteristics due to elevated sex hormones before the age of 6-8 in girls and 9 in boys. Excess hormone secretion may occur only at the level of the sex hormone or may involve the whole hypothalamic-pituitary-gonadal axis. Precocious Puberty, gynecomastia Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Gynecomastia, anovulatory infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility, and several gynecologic complaints. Adverse effects include hot flashes, venous thromboembolic events, bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones mineral density loss, and ischemic cardiovascular events. Antiestrogens are contraindicated in individuals with known hypersensitivity reactions and pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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Classification

Several main classes of antiestrogens are to be considered. Prototypical drugs in each class are noted with an asterisk (*).

  • Selective estrogen receptor modulators (SERMs):
    • Antagonist (i.e., antiestrogenic) activity in some tissues and agonist (i.e., estrogenic) activity in other tissues
    • Agents:
      • Tamoxifen*
      • Raloxifene
      • Ospemifene
      • Bazedoxifene
      • Clomiphene citrate
  • Selective estrogen receptor downregulators (SERDs):
    • Also known as pure estrogen antagonists
    • Only have antagonist activity
    • Agents: 
      • Fulvestrant* (the only FDA approved compound)
      • Several additional compounds are currently being developed and/or undergoing clinical trials.
  • Aromatase inhibitors:
    • Anastrozole*
    • Letrozole
    • Exemestane
  • Others:
    • Gonadotropin-releasing hormone (GnRH) analogues:
      • Leuprolide
      • Ganirelix
      • Elagolix
    • Androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens: Danazol 
    • Progestins
Overview of the antiestrogens and their actions

Overview of the antiestrogens and associated actions
GnRH: gonadotropin-releasing hormone
SERM: selective estrogen receptor modulators
FSH: follicle stimulating hormone
LH: luteinizing hormone
SERD: selective estrogen receptor downregulators

Image by Lecturio.

Selective Estrogen Receptor Modulators and Selective Estrogen Receptor Downregulators

Mechanism of action of SERMs

Tamoxifen, raloxifene, ospemifene, bazedoxifene, and clomiphene citrate:

  • Competitively bind to estrogen receptors (ERs)
  • Both agonist and antagonist activity, depending on the target tissue:
    • Antiestrogenic activity on the breast
    • Tend to have estrogenic (i.e. agonist) activity in:
      • Uterus
      • Bones
      • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver 
  • Estrogen receptors:
    • Located in the nucleus (rather than on the cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane)
    • Act as ligand-dependent transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription factor (when estrogen is the ligand required for DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure binding)
    • When estrogen binds to the ER, the ER-estrogen complex binds to the estrogen-response elements (EREs) in the promoter region of target genes.
    • Binding to the ERE may activate or repress the expression of the target gene.
  • How SERM effects differ between tissues is incompletely understood.
  • Theory: The SERM-ER complex interacts with different cofactors present in different tissues.

Mechanism of action of SERDs

Fulvestrant:

  • A high-affinity competitive antagonist preventing estrogen from binding to the ER
  • Similar to the endogenous estrogen ligand → competes with estrogen for binding to the ligand-binding domain of the ER
  • Pure ER antagonist activity with no agonist activity
  • Produces a complex within the cell nucleus (location of the ER), which causes downregulation of estrogen receptors
  • Dose-dependent effects (e.g., higher fulvestrant dose → more downregulation)
  • Without estrogenic stimulation → hormone-dependent tumor growth is inhibited

Physiologic effects

SERMs act as estrogen agonists in some tissues and estrogen antagonists in others.

Table: Physiologic effects of SERMs
Tissue Normal effects of estrogen Effects of SERMs
Breast
  • Stimulates breast growth
  • Is a risk factor for breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
Antagonist effects:
  • ↓ Estrogenic stimulation
  • ↓ Risk of breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer/recurrence
Hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus and pituitary Inhibits the release of GnRH and the gonadotropins (i.e., FSH, LH) Antagonist effects: ↓ inhibition of FSH/LH → ↑ FSH/LH release → ↑ follicular development and ovulation
Bone ↑ BMD Agonist effects: protects against the loss of BMD in the hypoestrogenic state of menopause Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause
Uterus
  • Stimulates endometrial growth
  • Is a risk factor for endometrial cancer Endometrial Cancer Endometrial carcinoma (EC) is the most common gynecologic malignancy in the developed world, and it has several histologic types. Endometrioid carcinoma (known as type 1 EC) typically develops from atypical endometrial hyperplasia, is hormonally responsive, and carries a favorable prognosis. Endometrial Hyperplasia and Endometrial Cancer
  • Agonist effects of tamoxifen and ospemifene: ↑ risk of endometrial hyperplasia Endometrial Hyperplasia Endometrial hyperplasia (EH) is the abnormal growth of the uterine endometrium. This abnormal growth may be due to estrogen stimulation or genetic mutations leading to uncontrolled proliferation. Endometrial Hyperplasia and Endometrial Cancer and/or cancer
  • Raloxifene: No significant effects
Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
  • Improves lipid profile:
    • ↑ HDL
    • ↓ LDL
    • ↓ Total cholesterol
  • ↑ Clotting factors → ↑ risk of VTEs
Agonist effects:
  • Maintains better lipid profiles
  • ↑ Risk of VTE
GnRH = gonadotropin-releasing hormone
FSH: follicle stimulating hormone
LH: luteinizing hormone
BMD: bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones mineral density
LDL: low-density lipoprotein
HDL: high-density lipoprotein
VTE: venous thromboembolism

Physiologic effects of SERDs:

Fulvestrant has purely antiestrogenic effects on tissues. Key physiologic effects include:

  • ↓ Estrogenic stimulation to the breast
  • ↓ Bone mineral density (BMD)
  • Suppression of endometrial growth

Pharmacokinetics

  • Absorption:
    • Rapidly absorbed when taken orally
    • Most have low bioavailability (< 10%)
  • Distribution:
    • Widely distributed
    • Highly protein-bound (primarily to albumin, not sex hormone-binding globulin)
  • Metabolism:
    • Hepatic metabolism
    • Tamoxifen: via CYP2D6 and CYP3A4/CYP3A5 to more potent active metabolites
    • Raloxifene: undergoes extensive 1st-pass metabolism to glucuronide conjugates
    • Bazedoxifene: hepatic metabolism (not via CYP enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes)
    • Ospemifene: via CYP3A4, CYP2C9, and CYP2C19
    • Fulvestrant: via CYP3A4 to active metabolites
  • Excretion:
    • Primarily fecal
    • Half-life: generally long:
      • Tamoxifen: 5–7 days
      • Raloxifene and bazedoxifene: approximately 30 hours 
      • Fulvestrant: approximately 40 days

Indications

Primary indications for each drug are indicated with an asterisk (*):

  • Breast cancer and other breast issues:
    • Agents:
      • Tamoxifen*
      • Raloxifene
      • Fulvestrant*
    • Adjuvant treatment in breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
    • Ductal carcinoma in situ (DCIS)
    • Prophylactic risk reduction in high-risk individuals
    • Gynecomastia (breast growth in men)
    • Severe mastalgia (breast pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain)
  • Postmenopausal osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis prevention and treatment: 
    • Raloxifene*
    • Bazedoxifene*
  • Other menopausal symptoms:
    • Bazedoxifene: vasomotor symptoms* (e.g., hot flashes, night sweats)
    • Ospemifene: vaginal dryness*
  • Infertility:
    • Clomiphene: for ovulation induction*
    • Tamoxifen:
      • For ovulation induction in individuals with breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
      • For idiopathic male factor infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility
  • Precocious puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty (e.g., McCune-Albright Syndrome):
    • 1st-line treatment: aromatase inhibitors
    • 2nd-line agents:
      • Tamoxifen
      • Fulvestrant
Mccune-albright syndrome

McCune-Albright syndrome:
McCune-Albright syndrome presents with a classic triad. The triad includes peripheral precocious puberty Precocious puberty Precocious puberty (PP) is the appearance of secondary sexual characteristics due to elevated sex hormones before the age of 6-8 in girls and 9 in boys. Excess hormone secretion may occur only at the level of the sex hormone or may involve the whole hypothalamic-pituitary-gonadal axis. Precocious Puberty, fibrous dysplasia of the bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones, and café au lait skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin hyperpigmentation, which is often found at the nape of the neck and the crease of the buttocks.

Image: “Skin hyperpigmentation” by Claudia E. Dumitrescu, & Michael T. Collins. License: CC BY 2.0

Adverse effects

  • Hot flashes (common with all SERMs and SERDs)
  • Venous thromboembolism (VTE) (a concern with all agents):
    • Deep venous thrombosis
    • Pulmonary embolism Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. Pulmonary Embolism
  • Uterine malignancies and lesions (tamoxifen, ospemifene, clomiphene):
    • Endometrial carcinoma
    • Uterine carcinoma (sarcoma)
    • Endometrial polyps Endometrial polyps Endometrial polyps are pedunculated or sessile projections of the endometrium that result from overgrowth of endometrial glands and stroma around a central vascular stalk. Endometrial polyps are a few millimeters to a few centimeters in size, can occur anywhere within the uterine cavity, and, while usually benign, can be malignant, particularly in postmenopausal women. Endometrial Polyps
    • Endometrial hyperplasia
    • Uterine fibroids
  • Ocular effects (tamoxifen)
  • Other common side effects (all agents):
    • 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
    • Dizziness
    • GI upset
    • Muscle spasms
    • Arthralgias/ bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain

Contraindications

  • Hypersensitivity
  • History or current VTE
  • Pregnancy
  • Unexplained vaginal bleeding
  • Concurrent warfarin therapy (tamoxifen)
  • Use with caution in hepatic impairment.

Aromatase Inhibitors

Overview

Aromatase inhibitors prevent the conversion of testosterone to estrogen, which is a process known as aromatization. Drugs in the class include anastrozole, letrozole, and exemestane. The medications are most commonly used in the treatment of postmenopausal breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer.

Mechanism of action

  • Aromatase inhibitors inhibit the action of aromatase: 
    • Anastrozole and letrozole: reversibly binds aromatase
    • Exemestane: irreversibly binds aromatase
  • Leads to ↓ estrogen levels in postmenopausal women:
    • Estrogen stimulates tumor growth in many breast cancers.
    • The overall effect of aromatase inhibitors:
      • Decrease tumor mass 
      • Delay progression in tumors responsive to hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview
  • Aromatase:
    • The key enzyme required in estrogen synthesis
    • Converts androgens into estrogens:
      • Blocks testosterone → estradiol
      • Blocks androstenedione → estrone
    • Located within:
      • Granulosa cells in the ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries (major site of estrogen production in premenopausal women)
      • Breast
      • Adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or "brite" adipose tissue, which is a transitional form. Adipose Tissue
      • Adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands 
      • Brain
      • Bone
  • Why aromatase inhibitors are used in postmenopausal women:
    • Prior to menopause Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause, the hypothalamic-pituitary-ovarian (HPO) axis is functional and responsive.
    • Inhibiting gonadal estrogen production → ↓ circulating estrogen → less inhibition of:
      • GnRH
      • Follicle stimulating hormone (FSH)
      • Luteinizing hormone (LH)
    • Less inhibition of GnRH, FSH, and LH → ↑ GnRH, FSH, and LH → stimulates ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries to ↑ androgen production 
    • The HPO axis “turns off” at menopause Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause with the cessation of ovarian function.
    • Extragonadal sites continue to produce estrogen capable of stimulating breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer in postmenopausal women → aromatase inhibitors inhibit estrogen production

Pharmacokinetics

Anastrozole, Letrozole:

  • Absorption (both):
    • Well absorbed orally
    • Rapid absorption
    • The extent of absorption is not affected by food.
  • Protein-binding (both): weak to moderate 
  • Metabolism:
    • Hepatic metabolism to inactive metabolites
    • Anastrozole: via N-dealkylation, hydroxylation, and glucuronidation 
    • Letrozole: via CYP3A4 and CYP2A6 
  • Excretion (both):
    • Primarily fecal (10% urine)
    • Half-life: approximately 2 days

Exemestane:

  • Absorption:
    • Moderately well absorbed following oral administration
    • ↑ Postprandial
  • Distribution:
    • Extensively distributed in tissues
    • 90% is protein-bound (primarily to albumin and ?1-acid glycoprotein)
  • Metabolism:
    • Extensive hepatic metabolism to inactive metabolites
    • Via CYP3A4 oxidation and reduction of 17-keto group
  • Excretion:
    • Roughly split between urine (primarily as metabolites) and feces
    • Half-life: approximately 24 hours

Indications

  • Advanced breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer in postmenopausal women
  • Risk reduction of breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer in postmenopausal women
  • Off-label use in recurrent ovarian and uterine cancers
  • Additional indications for letrozole: 
    • Infertility: 1st-line agent for ovulation induction in anovulatory women with polycystic ovarian syndrome Polycystic ovarian syndrome Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of reproductive-age women, affecting nearly 5%-10% of women in the age group. It is characterized by hyperandrogenism, chronic anovulation leading to oligomenorrhea (or amenorrhea), and metabolic dysfunction. Polycystic Ovarian Syndrome ( PCOS PCOS Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of reproductive-age women, affecting nearly 5%-10% of women in the age group. It is characterized by hyperandrogenism, chronic anovulation leading to oligomenorrhea (or amenorrhea), and metabolic dysfunction. Polycystic Ovarian Syndrome)
    • Peripheral precocious puberty Precocious puberty Precocious puberty (PP) is the appearance of secondary sexual characteristics due to elevated sex hormones before the age of 6-8 in girls and 9 in boys. Excess hormone secretion may occur only at the level of the sex hormone or may involve the whole hypothalamic-pituitary-gonadal axis. Precocious Puberty (e.g., McCune-Albright syndrome)

Adverse effects

  • Hot flashes
  • Sexual dysfunction (typically due to atrophic vaginitis)
  • Osteoporosis/osteopenia: ↓ BMD and ↑ fracture Fracture A fracture is a disruption of the cortex of any bone and periosteum and is commonly due to mechanical stress after an injury or accident. Open fractures due to trauma can be a medical emergency. Fractures are frequently associated with automobile accidents, workplace injuries, and trauma. Overview of Bone Fractures risk
  • Musculoskeletal effects:
    • Arthralgia/ bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Joint stiffness
    • Myalgias
    • Carpal tunnel syndrome Carpal Tunnel Syndrome Carpal tunnel syndrome (CTS) is a complex of signs and symptoms caused by compression of the median nerve as it crosses the carpal tunnel. Presentation is with pain and paresthesia of the dermatomal target tissues innervated by the median nerve as well as weakness and atrophy of the nerve's myotomal targets. Carpal Tunnel Syndrome
  • Peripheral edema
  • Gastrointestinal distress:
    • Nausea/vomiting
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea/ constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
    • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Weight gain
  • Hypercholesterolemia
  • Ischemic cardiovascular events (studies are mixed):
    • Likely ↑ risk in individuals with preexisting cardiovascular disease
    • ↑ Risk compared to tamoxifen (likely not a large ↑ risk compared to a placebo)
    • Events may include:
      • Angina pectoris
      • Acute myocardial infarction Myocardial infarction MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction
      • Ischemic stroke Ischemic Stroke An ischemic stroke (also known as cerebrovascular accident) is an acute neurologic injury that occurs as a result of brain ischemia; this condition may be due to cerebral blood vessel occlusion by thrombosis or embolism, or rarely due to systemic hypoperfusion. Ischemic Stroke

Contraindications

  • Hypersensitivity
  • Pregnancy
  • Breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding
  • Premenopausal status in use for breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer treatment

Gonadotropin-Releasing Hormone Analogues

Overview

  • GnRH is a key component of the HPO axis:
    • The hypothalamus releases GnRH.
    • GnRH stimulates the release of FSH and LH from the anterior pituitary.
    • FSH and LH stimulate the ovary, which produces estrogen and progesterone.
  • GnRH is released in a pulsatile fashion from the hypothalamus.
  • GnRH analogues bind to GnRH receptors in the pituitary.
  • Both agonists and antagonists suppress FSH and LH release, leading to suppression of:
    • Follicle development 
    • Ovulation
    • Estrogen and progesterone production
  • Should not be used as contraception
  • Adverse effects are similar to other antiestrogens:
    • Hot flashes
    • Night sweats
    • Mood swings
    • Vaginal dryness
    • Bone loss (treatment is often limited to < 6 months)

GnRH agonists

Leuprolide:

  • Continuous exposure (rather than pulsatile exposure) to GnRH suppresses FSH and LH → ↓ follicle development → ↓ estrogen
  • Creates reversible “medical menopause Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause” until the effects wear off
  • Suppression takes a few days → individuals often experience symptom “flares” prior to improvement
  • Given as IM injections every 1–3 months 
  • Indications:
    • Central precocious puberty Precocious puberty Precocious puberty (PP) is the appearance of secondary sexual characteristics due to elevated sex hormones before the age of 6-8 in girls and 9 in boys. Excess hormone secretion may occur only at the level of the sex hormone or may involve the whole hypothalamic-pituitary-gonadal axis. Precocious Puberty
    • Short-term (< 6 months) treatment of uterine fibroids:
      • Reduce fibroid size prior to surgery
      • Stop heavy menstrual bleeding to allow time for correction of 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 prior to surgery
      • Suppress symptoms until natural menopause Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause occurs in perimenopausal women
    • Short-term (< 6 months) treatment of endometriosis Endometriosis Endometriosis is a common disease in which patients have endometrial tissue implanted outside of the uterus. Endometrial implants can occur anywhere in the pelvis, including the ovaries, the broad and uterosacral ligaments, the pelvic peritoneum, and the urinary and gastrointestinal tracts. Endometriosis (e.g., to “burn out” implants prior to starting hormonal contraceptives Hormonal contraceptives Hormonal contraceptives (HCs) contain synthetic analogs of the reproductive hormones estrogen and progesterone, which may be used either in combination or in progestin-only formulations for contraception. Hormonal Contraceptives as a long-term treatment)
    • Treatment of advanced prostate cancer Prostate cancer Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of death is 2.5%. Prostate cancer is a slow-growing cancer that takes years, or even decades, to develop into advanced disease. Prostate Cancer

GnRH antagonists

Ganirelix, Elagolix:

  • Competitively block GnRH receptors on the pituitary 
  • Suppress FSH and LH release to prevent ovulation
  • Do not have the “flare” associated with GnRH agonists
  • Indications:
    • Ganirelix: Used as part of fertility treatments during controlled ovulatory cycles (other medications are given to develop follicles and trigger ovulation)
    • Elagolix: 
      • Endometriosis
      • Dyspareunia (painful intercourse)

Androgens and Progestins

  • Androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens and synthetic progestins (structurally similar to androgens) oppose estrogen in endometrial tissue.
  • Suppress endometrial growth → cause a thinning of endometrial tissue
  • Due to androgenic side effects, androgens are rarely used for treatment in women.
  • Progestins are a primary component of most hormonal contraceptives Hormonal contraceptives Hormonal contraceptives (HCs) contain synthetic analogs of the reproductive hormones estrogen and progesterone, which may be used either in combination or in progestin-only formulations for contraception. Hormonal Contraceptives.
  • Indications:
    • Contraception 
    • Conditions improving when endometrial growth is suppressed:
      • Endometriosis
      • Dysmenorrhea
      • Heavy menstrual bleeding
      • Endometrial hyperplasia

Comparison of Medications

Table: Comparison of antiestrogen medications
Medication Drug class Mechanism of action Indications Notes
Selective estrogen receptor modulators (SERMs) Tamoxifen
  • Competes with estrogen at the estrogen receptors
  • Antagonist effects in breast tissue but agonist effects in other tissue
Treatment of hormone receptor-positive breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer in premenopausal women Increase risk of endometrial cancer Endometrial Cancer Endometrial carcinoma (EC) is the most common gynecologic malignancy in the developed world, and it has several histologic types. Endometrioid carcinoma (known as type 1 EC) typically develops from atypical endometrial hyperplasia, is hormonally responsive, and carries a favorable prognosis. Endometrial Hyperplasia and Endometrial Cancer
Raloxifene
  • Prevention/treatment of osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
  • Reduce risk for invasive breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
No significant effect on endometrial growth
Selective estrogen receptor downregulators (SERDs) Fulvestrant “Pure” competitive antagonist of estrogen at estrogen receptors Breast cancer
  • No agonist activity
  • Useful in individuals:
    • With resistance to tamoxifen
    • With risks for endometrial cancer Endometrial Cancer Endometrial carcinoma (EC) is the most common gynecologic malignancy in the developed world, and it has several histologic types. Endometrioid carcinoma (known as type 1 EC) typically develops from atypical endometrial hyperplasia, is hormonally responsive, and carries a favorable prognosis. Endometrial Hyperplasia and Endometrial Cancer
Aromatase inhibitors Anastrozole Nonsteroidal competitive aromatase inhibitor Breast cancer in postmenopausal women Adverse effects include:
  • Bone mineral density loss → ↑ risk of osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
  • Musculoskeletal effects:
    • Arthralgias
    • Myalgias
    • Carpal tunnel syndrome Carpal Tunnel Syndrome Carpal tunnel syndrome (CTS) is a complex of signs and symptoms caused by compression of the median nerve as it crosses the carpal tunnel. Presentation is with pain and paresthesia of the dermatomal target tissues innervated by the median nerve as well as weakness and atrophy of the nerve's myotomal targets. Carpal Tunnel Syndrome
Exemestane Irreversible aromatase inhibitor
Gonadotropin-releasing hormone (GnRH) analogues Leuprolide GnRH agonist → continuous administration suppresses follicle-stimulating hormone (FSH) and luteinizing hormone (LH)
  • Precocious puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty
  • Uterine fibroids
  • Endometriosis
  • Advanced prostate cancer Prostate cancer Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of death is 2.5%. Prostate cancer is a slow-growing cancer that takes years, or even decades, to develop into advanced disease. Prostate Cancer
  • Given as injections every 1–3 months
  • Creates a reversible “medically induced menopause Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause
Elagolix Direct GnRH antagonist → suppresses FSH/LH
  • Endometriosis
  • Dyspareunia
Doses are lower → menopausal side effects are less than with leuprolide

References

  1. Fuqua, S. A. W., et al. (2021). Mechanisms of action of selective estrogen receptor modulators and down-regulators. In Burstein, H. J., et al. (Eds.), UpToDate. Retrieved on August 4, 2021, from https://www.uptodate.com/contents/mechanisms-of-action-of-selective-estrogen-receptor-modulators-and-down-regulators
  2. Sharma, P. (2020). Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention. In Hayes, D.F., et al. (Eds.), UpToDate. Retrieved on August 3, 2021, from https://www.uptodate.com/contents/selective-estrogen-receptor-modulators-and-aromatase-inhibitors-for-breast-cancer-prevention
  3. Rosen, H. N. (2019). Selective estrogen receptor modulators for prevention and treatment of osteoporosis. In Rosen, C. J., et al. (Eds.), UpToDate. Retrieved on August 3, 2021, from https://www.uptodate.com/contents/selective-estrogen-receptor-modulators-for-prevention-and-treatment-of-osteoporosis
  4. Pritchard, K. I. (2021). Adjuvant endocrine therapy in postmenopausal women with hormone receptor-positive breast cancer. In Hayes, D. F., et al. (Eds.), UpToDate. Retrieved on August 4, 2021, from https://www.uptodate.com/contents/adjuvant-endocrine-therapy-for-postmenopausal-women-with-hormone-receptor-positive-breast-cancer
  5. Conzen, S. D. (2021). Managing the side effects of tamoxifen and aromatase inhibitors. In Hayes, D. F., et al. (Eds.), UpToDate. Retrieved on August 4, 2021, from https://www.uptodate.com/contents/managing-the-side-effects-of-tamoxifen-and-aromatase-inhibitors
  6. Harrington, J., & Palmert, M. (2020). Treatment of precocious puberty. In UpToDate. Retrieved October 20, 2021, from https://www.uptodate.com/contents/treatment-of-precocious-puberty 
  7. Lexicomp Drug Information Sheets (2021). In UpToDate. Retrieved October 20, 2021, from:

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