Hormone Replacement Therapy PDF

Dr Gayana Amiyangoda Department of Pharmacology 30.08.2024  Premature menopause (also known as premature ovarian insufficiency or primary ovarian insufficiency) occurs when a woman’s ovaries stop functioning and...

Dr Gayana Amiyangoda Department of Pharmacology 30.08.2024  Premature menopause (also known as premature ovarian insufficiency or primary ovarian insufficiency) occurs when a woman’s ovaries stop functioning and menstruation ends before the age of 40. This leads to a drop in estrogen levels and the early onset of menopausal symptoms. Several factors can cause or contribute to premature menopause: 1. Genetic Factors: Menapause Family history: Women with a family history of early menopause are at a higher risk. Turner syndrome: A genetic disorder in which a woman is born with a missing or incomplete X chromosome, leading to ovarian dysfunction. Fragile X syndrome: Carriers of a pre-mutation of this genetic disorder can have an increased risk of premature menopause. 2. Autoimmune Diseases: In some cases, the body’s immune system attacks the ovaries, leading to ovarian failure. This can occur in diseases like: Thyroid disorders (e.g., Hashimoto’s thyroiditis) Rheumatoid arthritis Addison’s disease “Meno” – “pause” → menstruation – Type 1 diabetes 3. Medical Treatments: stop Chemotherapy and radiation therapy: These treatments, often used for cancer, can damage the ovaries and lead to early ovarian failure. Surgical removal of the ovaries (oophorectomy): When both ovaries are surgically removed, menopause occurs immediately, regardless of the woman’s age. Pelvic surgery: Certain surgeries involving the reproductive organs can inadvertently damage the ovaries, leading to premature menopause. Can be due to natural aging ( normal 4. Infections: Severe infections can sometimes cause ovarian damage, including: Mumps menapause) or premature Tuberculosis Cytomegalovirus (CMV) These infections are rare but can lead to premature ovarian insufficiency in some cases. menapause 5. Lifestyle Factors: Smoking: Smoking has been strongly linked to an earlier onset of menopause. It accelerates the depletion of ovarian follicles and lowers estrogen levels. Undernutrition or eating disorders: Conditions such as anorexia nervosa or severe malnutrition can impact ovarian function and lead to early menopause. Not an abrupt process - 6. Chromosomal Abnormalities: In addition to Turner syndrome and Fragile X syndrome, other chromosomal abnormalities can contribute to menopausal transition (or premature ovarian insufficiency. 7. Idiopathic (Unknown Causes): In many cases, the exact cause of premature menopause remains unknown. This is referred to as idiopathic perimenopause) starts 3-4 years premature ovarian insufficiency. 8. Environmental Factors: before final menstrual period. Exposure to certain toxins such as pesticides, chemicals, and solvents may damage ovarian function and contribute to early menopause. 9. Epilepsy: Women with epilepsy have an increased risk of premature ovarian insufficiency, likely due to the effects of seizures on the hypothalamic-pituitary-ovarian axis. 10. Chromosomal Disorders: Disorders like galactosemia, a metabolic condition that affects the body’s ability to process the sugar galactose, can cause premature ovarian insufficiency. Additionally, the Menopausal transition decline in estrogen can affect the brain’s ability to use glucose efficiently, which may contribute to cognitive symptoms often reported during menopause, such as memory lapses and difficulty concentrating  Perimenopausal period is characterized by Irregular menstrual cycles Marked hormonal fluctuations, often accompanied by hot flashes, sleep disturbances, mood symptoms, and vaginal dryness Metabolic alterations -changes in lipids and bone loss begins – long term health problems Virtually all women experience the menstrual irregularity and hormonal fluctuations prior to clinical menopause; Up to 80 % → hot flashes (the most common menopausal symptom)  Symptoms and signs of menapause Genitourinary syndrome of Menstrual cycle and endocrine menopause changes Hypoactive Sexual Desire Vasomotor changes/hot flushes Disorder Long term consequences of Depression hormone insufficiency - Bone loss - Dementia Sleep disturbances - Cardiovascular disease - Dyslipidemia - Skin changes - Weight changes Cognitive problems HRT History of HRT 2024?  The recommendation to use the lowest effective dose of Hormone Replacement Therapy (HRT) for the shortest duration necessary is based on balancing the benefits and risks associated with the therapy. Here are the key reasons: Minimizing Risks: Cardiovascular Risks: Higher doses and prolonged use of HRT can increase the risk of heart disease, stroke, and blood clots. Breast Cancer: Long-term use of HRT, especially combined estrogen- Current Indications of HRT progestin therapy, is associated with an increased risk of breast cancer. Other Risks: There are also potential risks of gallbladder disease and other conditions. Maximizing Benefits: Symptom Relief: Using the lowest effective dose helps manage menopausal symptoms like hot flashes, night sweats, and genitourinary symptoms while minimizing exposure to hormones. Bone Health: Even at lower doses, HRT can help prevent bone loss and reduce the risk of osteoporosis. Individualized Treatment: Personal Health Profile: Each woman’s health profile is different, and the risks and benefits of HRT can vary. Tailoring the dose and duration helps optimize the therapy for individual needs. Regular Reevaluation: Periodic reassessment ensures that the therapy remains appropriate and adjustments can be made as needed. Treatment of moderate to severe vasomotor symptoms of menopause Treatment of genitourinary syndrome of menopause (ie,vaginal and vulvar atrophy) Osteoporosis prevention – in postmenopausal females when other therapies are not appropriate/intolerable and women < 60 years to reduce the risk of fracture Advisable to restrict treatment administration to the shortest period and the lowest dosage possible to control symptoms effectively Hormone Replacement Therapy Has a variety in routes, formulations, regimens and doses. Routes: Can be given orally or transdermally (creams, sprays, patches, vaginal rings, or subdermal pellets)  Oral versus transdermal estrogen Oral – significant first pass effect – conversion to intermediate and inactive metabolites. -Increased portal concentration of estradiol -Increases production of TBG, CBG, SHBG, TG, HDL, Clotting factors. - Higher doses are required compared to transdermal preparations - Cheep and available Transdermal – No first pass effect - No increased risk of clotting factors production/ increased protein production - Effective to control vasomotor symptoms and prevent osteopenia at a low dose compared to oral formulation Oral versus transdermal estrogen Formulations: Estrogen formulations. - oral or transdermal Progestogen formulations – Usually oral , also transdermal Compounded formulation – combines E+P Preparations for vulvovaginal therapy – Estrogen, DHEA  Estrogen Alone (For Hysterectomized Females): Indication: Women who have had a hysterectomy (i.e., no uterus). Reasoning: Since there is no endometrium (uterine lining), there is no risk of endometrial hyperplasia or endometrial cancer. Therefore, estrogen can be used on its own. Benefits: Estrogen helps relieve menopausal symptoms such as hot flashes, vaginal dryness, and bone loss (osteoporosis prevention). Forms: Estrogen can be administered as oral tablets, transdermal patches, gels, or vaginal preparations. Safety: Estrogen-alone therapy is considered safe for hysterectomized women without the need for progesterone, which would otherwise be required to counterbalance Regimens: estrogen’s effects on the endometrium. 2. Combined Estrogen + Progesterone (For Non-Hysterectomized Females): 1. Estrogen alone Indication: Women who still have their uterus. Reasoning: Estrogen alone can cause endometrial hyperplasia (overgrowth of the uterine lining) in women with an intact uterus, which increases the risk of endometrial cancer. Adding progesterone prevents this by thinning the endometrial lining and inducing regular - For hysterectomized females shedding. Benefits: Relieves menopausal symptoms while preventing the development of endometrial cancer. Forms: Estrogen and progesterone can be delivered in oral tablets, patches, or as 2. Combined E+P part of a combined regimen. – Non hysterectomized females → to prevent endometrial overgrowth. - Can be administrated either in a sequential / cyclic regimen or in a continuous one. sequential / cyclical regimen - alternation of a pure oestrogenic period to an oestro-progestative one, leading to withdrawal bleeding - 10 days of progestin treatment per month. Continuous regimen - Preferred in elderly females where monthly bleeding not required. Preparations: Various preparations of Estrogen and Progesterone available Either synthetic/ biologic Either derived from progesterone and testosterone for progesterone derivatives Estrogen Preparations 17 – beta estradiol – poor absorption orally→ for parenteral formulation Micronized 17-beta estradiol (oral) structurally identical (bioidentical) to the main product of the premenopausal ovary Conjugated equine estrogens (CEEs) – formed from main`s urine Esterified estrogen Ethynyl Estradiol- in almost all OCP – most potent E- so used in low doses in HRT formulations Efficacy not different among preparartions  Equivalent doses 0.625mg Conjugated equine estrogen 1 mg micronized 17-beta estradiol 0.05 mg/day transdermal 17-beta estradiol 1.25 mg piperazine estrone sulfate Estradiol gels and sprays are available in different strengths Estrogen – mechanism of action  Oral Spray Patch Vaginal ring gel Drug- Drug interactions: Estrogens are partially metabolized by cytochrome P450 (CYP) 3A enzymes. Inhibitors of CYP3A increase serum levels of estrogens while CYP3A inducers can decrease concentrations of estrogens. Increases TBG leading to a higher percentage of protein-bound thyroxine (T4) and decreased serum levels of bioavailable T4. Progestogen Preparations Naturally occuring hormone- progesterone A progestogen is a molecule, either natural or synthetic, that shows similar effects as progesterone, binds to the progesterone receptor, and acts as an agonist. Progestins are synthetic progestogens. subclassified in 2 ways: (1) generationally or (2) based on structural properties. Structural Classification Pregnanes: medroxyprogesterone acetate, Progesterone nomegestrol acetate derivatives Estranes: ( more androgenic)Norethindrone, norethindrone acetate, ethynodiol diacetate, norethynodrel Testosterone derivatives Gonanes: levonorgestrel, desogestrel, Mainly used for norgestimate, gestodene contraception Generational Classification Progestegen Preparations for HRT Combined HRT preparations Sequential combined formulations: 1-2 mg oestradiol + 10mg dydrogesterone Elleste ( Femoston) 1-2 mg oestradiol + 1mg norethisterone acetate 1-2mg oestradiol + 1 mg norethisterone acetate Sequential therapy E and P separately Oral oestradiol 1 -2 mg + Micronised progesterone (taken separately): Utrogestan 200mg orally for 12 days a month at nigght Or Provera 10mg orally for 12 days a month Or Norethisterone 5mg orally for 12 days a month Or Mirena intrauterine system  Continous combined HRT 1-2 mg oestradiol + 100 mg progesterone( Femoston conti ) 1-2 mg oestradiol + 5mg dydrogesterone 1-2 mg oestradiol + 0.5mg norethisterone acetate 1-2 mg oestradiol + 2.5mg medroxyprogesterone acetate 1-2 mg oestradiol + 5mg medroxyprogesterone acetate Or can take E and P separately ( with low dose of P) Metabolism and Pharmacokinetics Oral progesterone undergoes hepatic first-pass metabolism (by P450 enzymes.) Plasma protein binding - free or bound to albumin and/or other transport proteins( Ex:testosterone derivatives bind to SHBG/CBG) Bioavailability – increased when micronized Oral - maximal serum concentrations within 1-3 hours T1/2 → varies based on progestogen type norethindrone – 8 hors drospirenone - 32.5 hours Adverse effects: Fluid retention Bloating Breast tenderness Headaches Mood changes Nausea. Lowering the dose or switching to a different estrogen/ progestogen therapy may help to relieve bothersome side effects. Benefits Vs Risk of HRT Cardiovascular health - Estradiol promotes vasodilatation , improved metabolic profile is likely responsible - Protection from cardiovascular events – when used early after menopause - Some RCT (WHI) – failed to show benefit – women were longer after menapause and elderly - “timing hypothesis” – early after menopause beneficial – reduction of atherosclerosis and cardiovascular events ( Less than 60 years of age and started < 10 years of menapause) - Blood pressure reduction – with drosperinone  Breast cancer risk - Cancer risk associated → can differ based on hormone formulation used, timing of initiation, and duration of hormone therapy use. - Estrogen → stimulates proliferation of breast tissue and breast cancer cells, yet high-dose estrogen can be used to treat breast cancer - WHI – showed increased risk in pts with CEE+MPA - Transdermal E reduced risk compared to oral E - WHI – “gap time hypothesis” → increased risk of breast cancer when E/E+P started less than 5 years ( particularly 1 year) of menopause compared to longer time from menopause  Endometrial cancer(EC) - Generally, hormonally responsive cancers and women with an unbalanced oestrogen exposure are at increased risk. - When used for less than 5 years, the sequential E+P regimen showed a decreased risk for EC, while continuing treatment after 5 years resulted in an increased risk for EC  Venous thromboembolism - Increased with oral formulations due to its higher concentration in the liver - Increased production of coagulation and fibrinolysis factors, thrombin generation or induction of resistance to activated protein C Bone health - have proven HRT efficacy in reducing bone loss in menopausal women. Monitoring : for adverse effects Abnormal uterine bleeding Fluid retention Breast tenderness Headaches Mood changes Contraindications for HRT Contraindications for oral or transdermal estrogen-based therapies include: Known, suspected, or history of breast cancer Known or suspected history of other estrogen-based cancer (ie, uterine cancer); women who have had a hysterectomy and have no remaining evidence of disease are still candidates for HRT Active deep venous thrombosis (DVT) or a history of DVT or pulmonary embolism History of blood clotting disorder, the most common being Factor V Leiden mutation carriers Active or history of arterial thrombotic diseases (eg, myocardial infarction or stroke) Chronic liver disease or dysfunction Migraine with aura Not applicable for transvaginal therapy Relative contraindications: Uncontrolled blood pressure (≥180/110) and triglycerides (>400 mg/dL) – high risk of stroke Genitourinary syndrome of Menapause Multiple symptoms associated with decreased sex steroids in genitourinary tissues. (vaginal dryness or irritation, dyspareunia, impaired sexual functionDysuria, urinary urgency, recurrent urinary tract infections (UTIs) Dehydroepiandrosterone (DHEA), a precursor adrenal hormone, is converted to estrogens and androgens in peripheral tissues. Daily vaginal 0.5% DHEA 6.5 mg → improve symptoms of genitourinary syndrome of menopause while having little systemic effects Other treatment modalities for menopausal symptoms Tibolone A synthetic compound with mixed oestrogenic, progestogenic and androgenic activities an efficient option for vasomotor symptoms alleviation or prevention of BMD loss Selective oestrogen receptor modulators (SERMs). Has a variable oestrogen activity, acting as oestrogen agonists in some tissues while in other tissues they exert oestrogen antagonist effects. Examples of SERMs of interest in menopause treatment include raloxifene together with novel molecules like bazedoxifene, lasofoxifene or ospemifene.  Why Use SNRIs and SSRIs? HRT is the most effective treatment for managing vasomotor symptoms, but it is not suitable for everyone. HRT may be contraindicated in women with: SNRI and SSRI A history of breast cancer, endometrial cancer, or ovarian cancer. A history of thromboembolism or stroke. Cardiovascular disease or high risk of cardiovascular events. Other hormone-sensitive conditions. In these cases, non-hormonal therapies like SSRIs and SNRIs can be effective alternatives for reducing the frequency and severity of hot flashes. SSRIs (Selective Serotonin Reuptake Inhibitors): Mechanism of Action: SSRIs work by increasing the levels of serotonin in the brain. Serotonin helps regulate mood, but it also plays a role in thermoregulation, which is important in controlling hot flashes. Common SSRIs for Vasomotor Symptoms: Paroxetine: This is the only SSRI FDA-approved specifically for the treatment of vasomotor symptoms in postmenopausal women. Fluoxetine and Citalopram: Also used off-label for hot flashes. When HRT is contraindicated can use these to control vasomotor women. Effectiveness: SSRIs can reduce the frequency and intensity of hot flashes by 50-60% in many symptoms Side Effects: Common side effects include nausea, fatigue, sleep disturbances, and sexual dysfunction. SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors): Mechanism of Action: SNRIs increase levels of both serotonin and norepinephrine, neurotransmitters involved in mood regulation and body temperature control. Increasing norepinephrine helps regulate thermoregulation more effectively, making SNRIs slightly more effective than SSRIs for hot flashes in some women. Common SNRIs for Vasomotor Symptoms: Venlafaxine: The most commonly used SNRI for treating hot flashes, especially in women who cannot take HRT. Desvenlafaxine: Also used for hot flashes. Effectiveness: SNRIs can reduce hot flashes by 40-60% and are typically well tolerated. Side Effects: Similar to SSRIs, including nausea, dry mouth, dizziness, and increased blood pressure (especially at higher doses). When to Use SNRIs/SSRIs: When HRT is contraindicated due to a personal or family history of cancer, cardiovascular disease, or thromboembolic disorders. For women who prefer not to use hormones. As a first-line treatment option in women who are only mildly to moderately affected by vasomotor symptoms.  Task… 1. How will you evaluate a patient before starting HRT and monitor after starting HRT ? Vasomotor symptoms (VMS) are among the most common and noticeable changes during menopause. These symptoms are primarily due to the fluctuating and declining levels of estrogen, which affect the body’s ability to regulate temperature. Here are the key vasomotor changes: Hot Flashes: Description: Sudden feelings of intense heat, often starting in the chest and face, and spreading to the rest of the body. Symptoms: Sweating, flushed skin, increased heart rate, and sometimes anxiety. After the heat, you might feel a chill12. Night Sweats: Description: Hot flashes that occur during sleep, leading to intense sweating. Symptoms: Disrupted sleep, waking up drenched in sweat, and needing to change clothes or bedding12. Heart Palpitations: Description: Irregular or rapid heartbeats that can accompany hot flashes. Symptoms: Feeling of the heart pounding or fluttering, which can be unsettling2. Causes The exact cause of vasomotor symptoms isn’t fully understood, but they are believed to be linked to the body’s thermoregulatory system becoming more sensitive due to hormonal changes. The decline in estrogen affects the hypothalamus, the part of the brain that regulates body temperature, leading to these symptoms12. Further reading: Smith, T., Sahni, S., & Thacker, H. L. (2020). Postmenopausal hormone therapy—local and systemic: a pharmacologic perspective. The Journal of Clinical Pharmacology, 60, S74-S85. Voican, A., Guiochon-Mantel, A., Francou, B., Meduri, G., Young, J., Bouligand, J.,... & Scarabin, P. Y. (2012). Pharmacology of hormone replacement therapy in menopause. INTECH Open Access Publisher. Pinkerton, J. V. (2020). Hormone therapy for postmenopausal women. New England Journal of Medicine, 382(5), 446-455.