Gyne Pharma Integration: Estrogens, Progesterone, and Clomiphene Citrate
Recombinant FSH, LH, and HCG
Apart from HMG, recombinant FSH, recombinant LH, and recombinant HCGs are available.
Recombinant FSH and LH are produced using genetic engineering techniques, offering higher purity compared to HMG but at a higher cost.
In patients with both LH and FSH deficiencies (hypogonadotropic hypogonadism), HMG is often preferred due to its cost-effectiveness, providing both hormones in a single formulation.
Recombinant FSH is available under the name ** **, recombinant LH is available under the name ** **, and recombinant HCG is available as choriogonadotropin alfa.
Estrogens
Synthetic Estrogens
Steroidal Derivatives:
Ethinyl estradiol: A potent synthetic estrogen commonly used in oral contraceptives.
Micronized 17 beta estradiol: A form of estradiol processed into smaller particles for better absorption.
Conjugated equine estrogens: A mixture of estrogen hormones derived from pregnant mare urine.
Nonsteroidal Derivatives:
Diethylstilbestrol: A synthetic estrogen formerly used to prevent miscarriages but now known to cause significant health issues.
Dinestrol: Another nonsteroidal estrogen, similar to diethylstilbestrol, with limited current use.
*Diethylstilbestrol (DES) is no longer used due to severe birth defects (congenital malformations) in both female and male fetuses.
Female Fetuses:
Cervical cancers: Increased risk of clear cell adenocarcinoma.
Vaginal cancers: Clear cell carcinoma of the vagina.
Clear cell carcinoma of the cervix
Hypoplastic uterus: Underdevelopment of the uterus.
T-shaped uterus: An abnormal uterine shape associated with fertility issues.
Male Fetuses:
Renal anomalies: Kidney abnormalities.
Cryptorchidism: Undescended testicles.
Problems related to DES are discussed in detail in the video on teratogenic exposure to the fetus.
Steroidal Derivatives (Ethinyl Estradiol, Micronized 17 Beta Estradiol, Conjugated Equine Estrogens)
Ethinyl estradiol is the most potent synthetic estrogen available and is widely used in oral contraceptives.
Natural estrogens potency: E2 > E1 > E3
Ethinyl estradiol is commonly used in oral combined pills (OCPs) due to its high potency and efficacy.
OCPs are categorized based on ethinyl estradiol dosage:
High dose: >50 mcg (no longer used due to thromboembolism risk)
Low dose: <50 mcg (mostly 30-35 mcg)
Very low dose: <20 mcg
The lowest effective contraceptive dose of ethinyl estradiol is 10 mcg.
Low doses are preferred due to the side effects of estrogen, such as increased clotting factors and thromboembolism risk, which are dose-dependent.
All synthetic estrogens are derived from plant sources except conjugated equine estrogen.
Conjugated equine estrogen is derived from the urine of pregnant mares and contains estrone (E1), making it less potent than ethinyl estradiol (E2). It is commonly used in hormone replacement therapy.
Dosage comparison: 0.625 mg of conjugated equine estrogen 5 mcg of ethinyl estradiol. This conversion helps in understanding the relative potency when switching between different estrogen formulations.
Uses of Estrogens
Contraception:
Oral combined pills (OCPs): Contain both estrogen and progestin to prevent ovulation.
Vaginal rings (e.g., Nuva Ring): Release a continuous low dose of estrogen and progestin.
Transdermal patches: Deliver hormones through the skin, providing a steady hormone level.
Hormone Replacement Therapy (HRT):
Treating hot flushes (vasomotor symptoms) in menopausal females by stabilizing hormone levels that fluctuate during menopause.
Theoretically can treat osteoporosis by increasing bone mass and inhibiting bone resorption, but it is not the first-line treatment due to potential risks.
Treating genitourinary symptoms (e.g., vaginal dryness) by increasing cervical mucus and improving vaginal tissue elasticity.
Atypical Uterine Bleeding (AUB): Estrogens can help regulate the menstrual cycle and reduce abnormal bleeding.
Non-Contraceptive Benefits of Oral Combined Pills: Many benefits are attributed to the estrogen component, such as improved bone density and reduced risk of certain cancers.
Methods of Estrogen Administration
Oral:
High first-pass metabolism, which reduces the bioavailability of the estrogen.
High portal vein estrogen concentration, leading to significant effects on liver function.
Increases production of:
Sex hormone binding globulin (SHBG): Reducing the amount of free estrogen.
Triglycerides: Increasing the risk of hypertriglyceridemia.
HDL: Generally increases, offering cardiovascular benefits.
Clotting factors: Increasing the risk of venous thromboembolism.
Transdermal:
As effective as oral estrogen in managing menopausal symptoms.
Lower risk of venous thromboembolism and stroke compared to oral administration.
Less effect on serum lipid concentration, making it a safer option for women with lipid disorders.
Preferred for HRT in postmenopausal females due to lower risks of VTE and stroke.
Topical Vaginal Estrogen:
Used to treat genitourinary symptoms such as dyspareunia (painful intercourse) and senile vaginitis by directly acting on the vaginal tissue.
Oral Combined Pills (OCPs)
Mechanism of Contraception
OCPs contain estrogen and progesterone (progestin).
Estrogen and progesterone from OCPs exert negative feedback on GnRH, reducing LH and FSH levels:
Decreased FSH inhibits folliculogenesis (follicle development), and decreased LH inhibits ovulation, resulting in anovulation.
Main mechanism: Inhibition of ovulation due to decreased FSH and LH, preventing egg release.
OCPs inhibit FSH more than LH, which is crucial for preventing follicular development.
Progesterone component thickens cervical mucus, creating a barrier to sperm, and decreases tubal motility, reducing the chance of fertilization.
Effect on Endometrial Thickness
Low-dose OCPs (e.g., 30 mcg ethinyl estradiol) reduce natural estrogen production, leading to a thinner endometrium.
Decrease GnRH, LH, and FSH, leading to decreased body's natural estrogen and therefore to anovulation.
Limited proliferation of the endometrium due to the small amount of estrogen in OCPs versus the lack of the body's estrogen.
Thinning of the endometrium contributes to the contraceptive effect by making it less suitable for implantation, even if fertilization occurs.
Administration of OCPs
Start on day one of the menstrual cycle (first day of bleeding) to ensure immediate contraception.
Take for three weeks (21 days), followed by one week off, allowing for a withdrawal bleed.
During the three weeks on OCPs, exogenous estrogen and progesterone are present; endogenous estrogen and progesterone are absent, maintaining hormonal balance.
Stopping OCPs causes a sudden drop in estrogen and progesterone, leading to menstruation (withdrawal bleeding).
OCPs can regularize irregular cycles by providing a consistent hormone level and predictable withdrawal bleeding.
Non-Contraceptive Benefits of OCPs
Regularizing cycles: Drug of choice for irregular cycles due to their consistent hormone delivery.
Decreasing excessive bleeding: Endometrial thinning reduces blood loss during menstruation.
Puberty menorrhagia: Excessive bleeding due to anovulatory cycles can be managed with OCPs by regulating the cycle and thinning the endometrium.
In puberty menorrhagia, there is estrogen breakthrough bleeding, which OCPs can control.
If vitals are stable, give OCPs to manage the bleeding.
If vitals are unstable, give IV estrogen followed by progesterone to quickly stabilize the endometrium.
Managing simple ovarian cysts: OCPs suppress the ovaries, reducing the formation of new cysts.
Treating hirsutism: OCPs decrease LH, reducing androgen production and alleviating symptoms of excess hair growth.
Adverse Effects of Estrogen
Nausea, vomiting: Common but usually mild and temporary.
Increased clotting factors: Can lead to thrombosis and thromboembolic events.
Contraindicated in patients with:
History of thromboembolism: Due to increased clotting risk.
History of stroke: Estrogen can increase the risk of stroke.
History of coronary artery diseases: Can exacerbate heart-related conditions.
Conditions predisposing to thromboembolism (e.g., prolonged immobility, lupus anticoagulant): These conditions increase the baseline risk of clotting.
Stimulates renin-angiotensin-aldosterone system: Leads to salt and water retention, causing mild hypertension.
Contraindicated in severe uncontrolled hypertension (BP ≥ 160/110 mmHg) due to the risk of further blood pressure elevation.
Cancers:
Endometrial cancer: Due to endometrial proliferation (estrogen alone).
Hepatic adenoma: Benign liver tumors.
Slight increase in breast cancer risk is associated with the progesterone component, not the estrogen component, during HRT.
In females with a uterus requiring HRT, give estrogen plus progesterone to protect against endometrial cancer. If the uterus is absent, give estrogen alone.
Progesterone is antiproliferative and therefore it is protective against endometrium cancer.
HRT should be used only for hot flushes interfering with daily life due to risks of endometrial cancer (estrogen alone) or increased breast cancer risk (estrogen + progesterone). The lowest effective dose should be used for the shortest possible duration.
Advantages of Estrogen
Increases bone mass: Helps prevent osteoporosis.
Relieves dryness of the vagina: Improving comfort and sexual function.
Relieves vasomotor symptoms: Reducing hot flushes and night sweats.
Selective Estrogen Receptor Modulators (SERMs)
Act as estrogen agonists in some tissues and antagonists in others, providing tissue-specific effects.
Examples: Clomiphene, tamoxifen, raloxifene, ospemifene, ormiloxifen, and basidoxifen.
Tamoxifen is used in surgery for breast cancer patients, acting as an estrogen antagonist in breast tissue.
Clomiphene citrate is commonly used in gynecology for managing PCOS and inducing ovulation.
Clomiphene Citrate
General Information
A selective estrogen receptor modulator used to induce ovulation.
A nonsteroidal triphenyl ethylene derivative.
Has two stereoisomers: cis (zooclomiphene) and trans (enclomiphene).
Clomiphene tablet composition:
60% enclomiphene (more potent, shorter half-life)
40% zuclomiphene (longer half-life)
Enclomiphene is more potent, has greater anti-estrogenic activity, and is responsible for follicular development, while zuclomiphene's longer half-life may contribute to prolonged effects.
Mechanism of Action
Centrally acting drug working on estrogen receptors in the hypothalamus.
Acts on estrogen receptors in the hypothalamus for a prolonged time, and downregulates them, disrupting the normal negative feedback.
Downregulation of estrogen in the hypothalamus decreases estrogen levels, leading to increased GnRH, FSH, and LH:
Decreased negative feedback on GnRH due to decreased estrogen, increasing GnRH, FSH, and LH levels, which are essential for ovulation.
Increased FSH promotes folliculogenesis, and increased LH promotes ovulation, helping to stimulate egg release.
Prerequisite: Functional hypothalamic-pituitary-ovarian (HPO) axis is necessary for clomiphene to work effectively.
Investigation for the level of LH and FSH
LH and FSH levels are useful to determine functionality of HBO access.
Clomiphene citrate can be used when either:
*Levels of LH and FSH are normal.
*Levels of LH and FSH are increased.
*Clomiphene citrate cannot be used when LH and FSH are decreased because it requires a functional HPO axis.
Indications for Clomiphene Citrate
PCOS: Drug of choice for anovulation in PCOS patients is letrozole, clomiphene is a first line drug.
Unexplained infertility: Used to stimulate ovulation in women with no known cause of infertility.
Drug of choice for any anovulation due to the causes where levels of LH and FSH are normal is clomiphene citrate
*In unexplained infertility, we use clomiphene with IUI to increase the chances of fertilization.
Anovulation where HPO axis is not intact:
Hypogonadotropic hypogonadism: Requires alternative treatments due to impaired GnRH production.
Absent GnRH (Kalman syndrome): Clomiphene is ineffective as the root cause is lack of GnRH.
Pituitary ablation: Requires alternative treatments because the pituitary gland is not functional.
*What to do in the places above? For these, either use pulsatile GnRH or HMG to stimulate ovulation.
Administration and Monitoring
Starting dose: 50 mg OD for five days to test the patient's response.
Maximum dose: 150 mg OD if lower doses are ineffective.
Begin on day 2 to day 5 of the cycle and give for five days to stimulate early follicular development.
LH surge typically occurs 5-12 days after stopping clomiphene, indicating impending ovulation.
Monitoring options after stopping clomiphene:
Daily intercourse for one week starting five days post cessation of therapy to maximize chances of conception.
*Urinary LH kits for surge detection to time intercourse effectively.
*With this method, have intercourse for four to five days around the time of the LH surge.
Follicular monitoring from day 10 to observe follicle size, on alternate days, using ultrasound.
Follicular Monitoring: Once the Follicle size becomes more than 15 mm, instruct daily intercourse for at least four to five days.
Typically, follicular monitoring is used in clinics:
*Follicular monitoring begins form day 10 of the cycle.
*Once follicle is between 18-20 mm, inject hCG (5000 units) to trigger ovulation.
Injection hCG (5000 units) acts like an LH surge, inducing ovulation 24 to 36 hours later.
Is it mandatory to give ovulate trigger injection hCG? No, it is optional.
Is it mandatory to do follicular monitoring in patient who are taking clonmefene? No, but it provides valuable information.
Rate of Ovulation & Pregnancy
Ovulation rate with clomiphene citrate: 80%.
*Pregnancy rate with clomiphene citrate: 30-40%.
*The reason for such discrepancy? CLOMIPHENE IS A SELECTIVE ESTROGEN RECEPTOR MODULATOR, affecting estrogen receptors in various tissues.
ALL of SERMs act as estrogen antagonists with uterus, vagina, and cervix, potentially reducing receptivity to implantation.
So, the endometrium is therefore less suitable and cervical mucus becomes thicker, hindering sperm transport.
In IVF cycles, HMG is mostly preferred injection since HMG increases estrogen, which is needed for a higher fertilization rate.
Adverse Effects of Clomiphene Citrate
Decreased estrogen:
Hot flushes (most common side effect) due to estrogen antagonism.
Dryness of vagina: Also due to estrogen antagonism.
Increased FSH:
Multi-fetal pregnancy (incidence 4-7% or 6-8%, mainly twin pregnancies) due to multiple follicles developing.
Ovarian hyperstimulation syndrome (rare, mild cases) due to excessive follicular development.
Centrally acting effects:
Headache: Common neurological side effect.
Visual disturbances (stop clomiphene immediately if visual symptoms occur) due to potential effects on the optic nerve.
*Ovarian cyst formation (second most common side effect) due to stimulated follicular growth.
Clomiphene citrate causes the following problems: no increased risk of teratogenicity, no increased risk of breast cancer, and no increased risk of ovary cancer.
Additional notes for Clomiphene Citrate
Clomiphene will be not as successful with someone is older than 35, BMI greater than 25, and presence of pre-existing hyperandrogenism.
*Insulin resistance (check with doing a 75 gram 2 hour OFTT) can be there the BMI is greater than 25, and it is preferred to give them metformin along with Clomiphene to improve ovulation rates.
*Give Gluocorticoids to those who have hyperandrogenism along with the clomiphene to reduce androgen levels.
Do not use these drug as ovulation induction drug instead of gluocorticoids, and metformin- use drugs such as prisolone or hydrocortison instead.
Always limit the number of cycles, which should be given to someone, the number should not be more than 6 to minimize the risk of side effects.