Noncontraceptive Estrogen and Progestins

Estrogen and progesterone are the sex 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 produced by 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 in premenopausal women. These agents are responsible for developing and maintaining female sex organs and secondary sexual characteristics. Estrogen and progesterone are used to treat hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism ( primary ovarian insufficiency Primary ovarian insufficiency Primary ovarian insufficiency (POI) is a condition resulting from the depletion or dysfunction of the ovarian follicles, leading to cessation of ovulation and menses before age 40. Primary ovarian insufficiency is primarily idiopathic. Patients present with signs and symptoms of menopause prior to age 40, including oligo- or amenorrhea, vaginal dryness (often leading to dyspareunia), and infertility. Primary Ovarian Insufficiency), menopausal symptoms, and gender dysphoria in transgender women. Risks and side effects include uterine bleeding, predisposition to cancer, breast tenderness, hyperpigmentation, migraines, hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, and mood changes. Contraindications are estrogen-dependent neoplasms, thromboembolic disorders, and 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 disease.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definitions

  • Estrogen is used as a generic term for any estrogenic agent (estrone, estradiol, and estriol); these agents can be synthesized by the human body or found in synthetic preparations used for medical therapy.
  • Unlike the term estrogen, progesterone is not a generic term. Progesterone refers only to the hormone synthesized by the corpus luteum. Micronized progesterone in pill form is chemically identical to progesterone of human ovarian origin. 
  • Progestins are synthetic progestational agents that are not identical to progesterone made by 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; examples are drospirenone, levonorgestrel, and medroxyprogesterone used in oral contraceptives, implants, and hormonal IUDs.

Classification

  • Natural steroid estrogens:
    • Estradiol (E2) is the  most potent estrogen: 
      • Produced primarily in 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; minute amount made from the 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 and the testes by aromatization of testosterone
      • Along with progesterone, regulates the menstrual cycle Menstrual cycle The menstrual cycle is the cyclic pattern of hormonal and tissular activity that prepares a suitable uterine environment for the fertilization and implantation of an ovum. The menstrual cycle involves both an endometrial and ovarian cycle that are dependent on one another for proper functioning. There are 2 phases of the ovarian cycle and 3 phases of the endometrial cycle. Menstrual Cycle
      • Maintains breast and uterine growth
      • Maintains 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
      • Plays a role in calcium homeostasis and has beneficial effects on 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
    • Estrone (E1):
      • Produced by the ovary
      • End product of estradiol metabolism
    • Estriol (E3):
      • Has no hormonal activity
      • Produced in the last trimester of 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 by placental conversion of fetal adrenal steroids
      • Relates to fetal well-being and placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity–fetus viability
  • Synthetic steroid: ethinyl estradiol
  • Synthetic nonsteroidal estrogen: diethylstilbestrol (DES); use has been discontinued, but it remains historically and clinically significant for daughters of mothers who used it
  • Natural progesterone: called micronized progesterone in pill form
  • Synthetic progestins:
    • Hydroxyprogesterone caproate
    • Medroxyprogesterone acetate
    • 19-nortestosterone derivatives:
      • Desogestrel
      • Norethindrone
      • Norethindrone acetate
      • Ethynodiol diacetate
      • Levonorgestrel
Overview of steroidogenesis pathways

Overview of the steroidogenesis pathways

Image by Lecturio.

Estrogens

In the body, estradiol is oxidized to estrone, and both estradiol and estrone can be converted to estriol. Estrone is a biologically active estrogen found in compounded medications and some pharmaceutical preparations used to treat menopausal symptoms. Estrone is prepared from the urine of pregnant mares (conjugated equine estrogen (CEE)).

Phytoestrogens (soy isoflavones) are plant-derived estrogens that bind less potently than estradiol to the estrogen receptor and are found in pharmaceutical and botanical/herbal preparations.

Mechanism of action

  • Estrogen in plasma and interstitial fluid:
    • Bound to sex hormone–binding globulin (SHBG)
    • Dissociates to enter cells and bind to their receptors
  • Hormone binds to its receptor → conformational alteration → release from the stabilizing proteins
  • Receptor–hormone complex forms homodimers → bind to a specific sequence of nucleotides (estrogen response elements) in the promoters of various genes → 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 regulation 
  • Indirect estrogen effects are mediated by autocrine and paracrine actions:
    • Growth factors
    • Lipids
    • Glycolipids
    • Cytokines
    • Produced by target cells in response to estrogen

Physiologic effects

  • Endometrial effects:
    • Plays a role in the development of the endometrial lining
    • Estrogen production is coordinated with progesterone during the normal menstrual cycle Menstrual cycle The menstrual cycle is the cyclic pattern of hormonal and tissular activity that prepares a suitable uterine environment for the fertilization and implantation of an ovum. The menstrual cycle involves both an endometrial and ovarian cycle that are dependent on one another for proper functioning. There are 2 phases of the ovarian cycle and 3 phases of the endometrial cycle. Menstrual Cycle for regular bleeding and shedding of the endometrial lining.
    • Continuous exposure →  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 abnormal uterine bleeding Abnormal Uterine Bleeding Abnormal uterine bleeding is the medical term for abnormalities in the frequency, volume, duration, and regularity of the menstrual cycle. Abnormal uterine bleeding is classified using the acronym PALM-COEIN, with PALM representing the structural causes and COEIN indicating the non-structural causes. Abnormal Uterine Bleeding
  • Metabolic and cardiovascular effects:
    • Partially responsible for maintenance of normal 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 and blood vessel structure
    • ↓ Rate of 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 resorption in individuals with 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
    • Positive effects on plasma lipids: ↑ HDL and ↓ total plasma cholesterol levels
  •  Effects on blood coagulation:
    • ↑ Circulating levels of factors II, VII, IX, and X
    • ↓ Antithrombin III
    • ↑ Plasminogen levels
    • ↓ Platelet adhesiveness
  • Other effects:
    • Induces synthesis of progesterone receptors
    • Has influences on mood and libido
    • Stimulates production of corticotropin-releasing hormone
    • Facilitates loss of intravascular fluid into the extracellular space → 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 
    • Modulates sympathetic nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System control of smooth muscle function

Pharmacokinetics

  • Available forms:
    • Oral:
      • Most preparations used are synthetic and derived from plant sources.
      • Conjugated equine estrogens derived from the urine of pregnant mares (brand name Premarin, both pills and vaginal cream) are still used but were more prevalent in past decades.
    • Topical:
      • No 1st-pass effect: lower risk profile
      • Steady-state plasma levels
      • Transdermal
      • Topical gels
      • Emulsions
      • Lotions
    • Intravaginal:
      • Indication: atrophic vulvovaginitis Vulvovaginitis The term vulvovaginitis is used to describe an acute inflammation of the vulva and vagina. Vulvovaginitis can be caused by several infectious and non-infectious etiologies, and results from disruption of the normal vaginal environment. Common signs and symptoms include pain, pruritis, erythema, edema, vaginal discharge and dyspareunia. Vulvovaginitis
      • No 1st-pass effect; lower risk profile
      • No need for progesterone replacement in most women
      • Forms: cream, tablet, vaginal ring
  • Absorption:
    • Oral:
      • High 1st-pass effect
      • Near constant serum estradiol concentrations between doses
      • ↑ Production of hepatic proteins
    • Transdermal and topical:
      • No 1st-pass effect
      • Rapid and complete absorption
    • Vaginal ring:
      • Rapid absorption during the 1st hour
      • Decreases to steady-state absorption over the next 3 months
  • Distribution:
    • 97% of estradiol in the blood is bound to plasma proteins:
      • Mainly bound to SHBG
      • Less affinity with albumin
    • ↑ Concentration in target organs
    • Bound estrogen:
      • Relatively unavailable for diffusion into cells
      • Free fraction is physiologically active
  • Metabolism:
    • Hepatic CYP3A4 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 
    • Enterohepatic recirculation → converted to active estrogen metabolites, including estrone
  • Excretion:
    • Urine 
    • Bile
  • Half-life:
    • Estradiol: 1‒2 hours
    • Estrone: 4‒18 hours
    • Extended absorption with transdermal, topical, and injectable forms

Indications

Estrogen products, with or without a progestin, are often prescribed to treat vasomotor and other symptoms associated with 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. These products are also indicated for younger women with premature ovarian failure. 

  • Primary ovarian insufficiency (POI)
    • Rationale:
      • Reduce the 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, cardiovascular disease, and genital atrophy
      • Maintain sexual health and quality of life
      • For women with POI  who also need contraception in addition to hormone replacement, oral contraceptives may be used.
    • Amenorrhea:
      • Girls with primary amenorrhea Primary Amenorrhea Primary amenorrhea is defined as the absence of menstruation in a girl by age 13 years in the absence of secondary sex characteristics or by the age of 15 years with the presence of secondary sex characteristics. Etiologies can originate in the hypothalamic-pituitary-ovarian (HPO) axis or from anatomic abnormalities in the uterus or vagina. Primary Amenorrhea and lack of secondary sex characteristics are initially treated with very low doses of estrogen (without a progestin at first) to simulate gradual pubertal maturation.
      • Women with secondary amenorrhea Secondary Amenorrhea Secondary amenorrhea is defined as the absence of menses for 3 months in a woman with previously regular menstrual cycles or for 6 months in a woman with previously irregular cycles. Etiologies involve either disruptions to the hypothalamic-pituitary-ovarian (HPO) axis or acquired obstructions in the uterus or outflow tract. Secondary Amenorrhea should receive full replacement doses of estrogen (doses higher than those used for postmenopausal symptoms).
  • Used in combination with progestins to suppress ovulation in individuals with:
    • Intractable dysmenorrhea
    • Hirsutism
    • Amenorrhea due to excessive ovarian androgen secretion
  • Menopausal hormone therapy (MHT):
    • Factors for consideration:
      • Age
      • Severity of symptoms
      • Individual’s risks for cardiovascular disease, thrombotic events, and 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
    • Primary objective is to treat hot flushes:
      • Most common indication: moderate to severe symptoms with a negative impact on quality of life
      • Mild symptoms do not require treatment.
    • Secondary objectives are to treat:
      • Vaginal dryness
      • Sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep disturbances
      • Mood lability
      • Depression
      • Joint 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
    • MHT safe:
      • For healthy women with moderate to severe symptoms
      • For women in the 1st 10 years 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 or ≤ 60 years of age (in general, not recommended for use in somen ≥ 65)
      • When there are no contraindications
    • Treatment regimens:
      • Estrogen without progesterone/progestin after hysterectomy
      • Combined estrogen–progestin therapy for women with an intact uterus to prevent estrogen-associated 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 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
    • Vulvovaginal atrophy (also called genitourinary syndrome 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):
      • Low-dose vaginal estrogen instead of systemic forms
      • Can be continued indefinitely once systemic hormone use has ceased
  • Transgender women: Estrogen is used in combination with antiandrogen therapy.

Adverse effects

  • Vaginal bleeding
  • Increased risk of breast and endometrial cancers
  • Breast tenderness
  • Skin hyperpigmentation
  • Migraine Migraine Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine Headache headaches
  • Cholestasis
  • Hypertension
  • Thromboembolic disease:
    • MI MI 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
    • Stroke ( cerebrovascular accident Cerebrovascular accident 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)
    • Deep vein thrombosis Deep vein thrombosis Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis ( DVT DVT Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis)

Contraindications

  • Breast and endometrial cancers
  • Coronary artery disease
  • Undiagnosed vaginal bleeding
  • Liver disease
  • Thromboembolic disorders
  • Stroke or transient ischemic attack Transient ischemic attack Transient ischemic attack (TIA) is a temporary episode of neurologic dysfunction caused by ischemia without infarction that resolves completely when blood supply is restored. Transient ischemic attack is a neurologic emergency that warrants urgent medical attention. Transient Ischemic Attack (TIA)
  • Tobacco smokers over age 35

Drug–drug interactions

  • Increased clearance of estrogens and other steroid 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:
    • Anticonvulsant Anticonvulsant Anticonvulsant drugs are pharmacological agents used to achieve seizure control and/or prevent seizure episodes. Anticonvulsants encompass various drugs with different mechanisms of action including ion-channel (Na+ and Ca+2) blocking and GABA reuptake inhibition. First-Generation Anticonvulsant Drugs drugs
    • Use transdermal estrogen to avoid the 1st-pass effect.
  • Estrogen causing an increase in thyroxine-binding globulin (TBG):
    • Decreases bioavailable thyroxine
    • Transdermal preparations are less offending
    • Individuals with hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism may need ↑ dose of thyroid replacement if also taking estrogen.
    • Monitor thyroid-stimulating hormone (TSH) levels.
  • ↑ Serum estradiol levels: 
    • Alcohol ingestion
    • End-stage kidney disease: important to reduce estrogen dosage

Progesterone and Progestin

Progesterone (bioidentical medication) and progestins (synthetic preparations) are often used with estrogens in women with menopausal symptoms who have not undergone hysterectomy.

Postmenopausal women without an intact uterus do not need a progestin, as there are no health benefits of progestin other than preventing 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 cancer.

Younger women with primary ovarian insufficiency Primary ovarian insufficiency Primary ovarian insufficiency (POI) is a condition resulting from the depletion or dysfunction of the ovarian follicles, leading to cessation of ovulation and menses before age 40. Primary ovarian insufficiency is primarily idiopathic. Patients present with signs and symptoms of menopause prior to age 40, including oligo- or amenorrhea, vaginal dryness (often leading to dyspareunia), and infertility. Primary Ovarian Insufficiency are treated with both estradiol and micronized progesterone to simulate normal ovarian function as much as possible.

Classification

  • Progesterone (made in the body):
    • Stimulates hair growth
    • Has antiandrogenic properties
    • May improve mood and sleep
    • Not known to increase the 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
  • Progestins (synthetically made from a plant source):
    • Can cause hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
    • Can cause hair loss
    • Some have androgenic properties
    • May have adverse effects on mood (e.g., anxiety, depression)
    • In combination with estrogen → increased 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
    • In combination with estrogen → possible increased risk of dementia in postmenopausal women > 64

Mechanism of action

  • Enters the cell → binds to progesterone receptors that are distributed between the nucleus and the cytoplasm
  • Progesterone–receptor complex forms a dimer before binding to 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.
  • Can form heterodimers as well as homodimers between isoforms A and B

Physiologic effects

  • Stimulates lipoprotein lipase activity and favors fat deposition
  • ↑ Basal insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin levels and insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin’s response to glucose
  • Promotes glycogen storage in the 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, possibly by facilitating the effect on insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin
  • Promotes ketogenesis
  • ↑ Secretion of aldosterone by the adrenal cortex
  • ↑ Body temperature
  • Affects mood and sleep (hypnotic effect)
  • Responsible for the development of the secretory apparatus in the breast
  • Participates in the preovulatory luteinizing hormone (LH) surge
  • Causes the maturation and secretory changes in the endometrium seen following ovulation

Pharmacokinetics

  • Available forms:
    • Oral
    • Implant (Nexplanon)
    • Injection (Depo-Provera)
    • Intrauterine (e.g., in intrauterine devices (IUDs))
    • Transdermal patch
    • Vaginal gel
  • Absorption: rapid following administration by any route
  • Distribution: 95% bound to serum albumin
  • Metabolism:
    • Completely metabolized in 1 passage through the 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
    • Progesterone is metabolized to pregnanediol and conjugated with glucuronic acid.
  • Excretion: 
    • Primarily in urine 
    • 10% in feces
  • Half-life: 16‒18 hours

Indications

  • MHT:
    • Used in combination with estrogen in women with an intact uterus to prevent 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 carcinoma caused by unopposed estrogen replacement therapy
    • Occasionally used for menopausal symptoms in women who cannot take estrogens
  • For long-term ovarian suppression causing prolonged anovulation and amenorrhea in treatment of:
    • Dysmenorrhea
    • 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
    • Bleeding disorders

Adverse effects

  • Hypertension
  • Chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain
  • Breast tenderness and hypertrophy
  • 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
  • Bloating
  • 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
  • Somnolence
  • Dizziness
  • Headache
  • Irritability
  • Depression
  • Irregular vaginal bleeding

Contraindications

  • History of or existing thromboembolic disorders
  • Breast or uterine carcinoma
  • Liver dysfunction

Drug–drug interactions

  • Progestins ↓ therapeutic effect:
    • Antidiabetes agents
    • Ulipristal: selective progesterone receptor modulator used as emergency contraception through inhibition of LH and ovulatory delay
    • Sincalide: diagnostic agent used for GI imaging
  • ↓ Therapeutic effect of progestins:
    • Ulipristal
    • Antifungal agents

Comparison of Medications

Table: Comparison of estrogens and progesterone/progestins
Estrogens Progesterone/progestins
Mechanism of action Bind to estrogen receptors, develop and maintain female sex characteristics and reproductive systems
  • Inhibit pituitary gonadotropin release, block follicular maturation and ovulation
  • Transform proliferative into secretory endometrium
Indications
  • Hypogonadism
  • Postmenopausal symptoms
  • Transgender women
  • Secondary amenorrhea
  • Prevention of postmenopausal 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 with estrogen use
  • Postcoital emergency contraception (alone or in combination with estrogen)
Side effects
  • Thromboembolism
  • Retinal thrombosis
  • MI MI 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
  • Stroke
  • Hypertension
  • Endometrial hyperplasia
  • Cholestasis
  • Depression
  • Migraine Migraine Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine Headache
  • Vaginal bleeding
  • 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
  • Nausea
  • Thromboembolism
  • Optic neuritis
  • MI MI 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
  • Stroke
  • Hypertension
  • Hepatic adenoma
  • Headache
  • Depression
  • 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
  • Nausea
  • Cholestasis
Contraindications
  • Undiagnosed vaginal bleeding
  • Pregnancy
  • Breast cancer, current or history of
  • Previous thromboembolic event ( DVT DVT Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis, PE, stroke)
  • Coronary heart disease Coronary heart disease Coronary heart disease (CHD), or ischemic heart disease, describes a situation in which an inadequate supply of blood to the myocardium exists due to a stenosis of the coronary arteries, typically from atherosclerosis. Coronary Heart Disease
  • Active 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 disease
  • History of venous thromboembolism or arterial thromboembolism < 12 months
  • Others same as listed for estrogens
DVT DVT Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis: deep vein thrombosis
PE: 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

References

  1. Martin KA, et al. (2021). Preparations for menopausal hormone therapy. UpToDate. Retrieved November 6, 2021, from https://www.uptodate.com/contents/preparations-for-menopausal-hormone-therapy
  2. Lee SR, et al. (2020). The 2020 menopausal hormone therapy guidelines. Journal of Menopausal Medicine 26(2):69-98. DOI: 10.6118/jmm.20000
  3. Pinkerton JV. (2019). Menopause. MSD Manual Professional Version. Retrieved November 6, 2021, from https://www.msdmanuals.com/professional/gynecology-and-obstetrics/menopause/menopause
  4. Chrousos GP. (2018). The gonadal hormones and inhibitors. In Katzung B.G. et al. (Ed.), Basic and Clinical Pharmacology, 14th ed., vol. 1, pp. 722–731. McGraw Hill.
  5. Martin KA, Barbieri R. (2021). Treatment of menopausal symptoms with hormone therapy. UpToDate. Retrieved November 6, 2021, from https://www.uptodate.com/contents/treatment-of-menopausal-symptoms-with-hormone-therapy
  6. Giordano Imbroll M, Gruppetta M. (2020). A current perspective into young female sex hormone replacement: a review. Expert Review of Endocrinology & Metabolism 15:405–414. DOI: 10.1080/17446651.2020.1816820

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