Estrogen and Ovarian Cycle Overview

Estrogens

• Natural human estrogens
• Phytoestrogens (Soy, saw palmetto)
• Estrogens in ocean sediments
• Phenols
• Used in plastic manufacturing
• Associated with increased breast cancer risk in both sexes

Ovarian Cycle

• Granulosa cells essential for stages of ovarian cycle
• Theca folliculi cells are also involved in production. (Stage 2)
• Primary oocyte in zona pellucida (Stage 3)
• Secondary oocyte and Corona radiata ( Stage 4 )
• Ovarian and Endometrial cycles
• Estrogen and progesterone levels fluctuate throughout the cycle. Graph shows hormone levels during cycles with and without conception.
• Various stages of follicular and luteal phases are shown with hormone measurements.
• Various stages detailed with a diagram relating to stages.

Natural Estrogens

• Estradiol (E2), Estrone (E1), Estriol (E3)
• E2 is the primary estrogen secreted by the ovaries
• E1 and E3 are primarily produced through liver conversion or from adrenal androgens
• Estrogen production occurs in ovarian follicles by theca and granulosa cells (pre-ovulation)
• Post-ovulation, estrogen is produced by theca and granulosa cells of the corpus luteum
• Progesterone also produced during ovulation
• Pregnancy involves estrogen production from the placenta and fetus
• Estrogen levels fluctuate monthly with the ovarian cycle (lowest in early follicular, highest right before ovulation)
• E2 has higher affinity for estrogen receptor compared to E1 and E3.

Estrogen Production

• Estrogen production involves the cooperation of theca and granulosa cells under regulatory LH (luteinizing hormone) and FSH (follicle-stimulating hormone)
• Cholesterol is the precursor to estrogen production in theca cells.
• Enzymes like 3β-HSD, 17α-hydroxylase, 17,20 lyase, and 17β-HSD play roles in converting cholesterol to pregnenolone then progesterone, Androstenedione and Testosterone.
• Aromatase enzyme in granulosa cells converts androgens to estrogens.

Estrogen Source

• Ovaries are the primary source of estrogen in premenopausal women
• Estrogen is primarily produced by adrenal glands in post-menopausal women (estrone).
• Also produced by ovarian follicles, corpus luteum and placenta with lesser amounts produced by liver, breast tissue and adrenal glands.

Pharmacokinetics

• Estrogens bind to SHBG (sex hormone-binding globulin) in the blood with high affinity and albumin with lower affinity
• Estrogen is converted to estrone and estriol in the liver and other tissues.
• Some estrogen derivatives (Estrone and Estriol) are secreted into bile.
• Oral estrogens have a higher ratio of liver to peripheral effects compared to Transdermal and Cream forms.
• Increased clotting factors and renin levels may occur with estrogen therapies.
• Estrogens are excreted into breast milk.

Synthetic Estrogens

• Chemical alterations are used to enhance oral efficacy
• Types of synthetic estrogens: steroidal and non-steroidal
• Some are prodrugs such as Quinestrol which produces Ethinyl estradiol
• Conjugated equine estrogens (Premarin, Enjuvia, Cenastin) are used
• Esterified forms of synthetic estrogens
• Non-steroidal Forms (diethylstilbestrol (Stilbestrol), dienestrol, benzestrol, hexestrol, chlorotrianisene
• Specific uses may differ for prostate cancer today.

Mechanism of Action

• Bound to SHBG in plasma, then dissociates to enter cells
• Travels to the nucleus and binds to estrogen receptor (ER)
• Estrogen binding causes dissociation of ER from HSP90
• ER and receptor-ligand complex dimerizes and binds estrogen response elements (EREs) on DNA
• Transactivation complex forms by recruitment of co-regulators and transcription factors (TFs).
• Two ER subtypes: alpha and beta
• Alpha has effects on uterus, breast tissue, bone maintenance, etc
• Beta has immune and nervous system effects.
• Estrogens have non-genomic effects and are responsible for rapid responses.

Physiological Effects

• Sexual maturation: estrogen stimulates growth and development, promotes development of genitalia (vagina, uterus, Fallopian tubes).
• Breast, uterine, and secondary sex characteristic development
• Endometrial effects: endometrial lining development is dependent on estrogen
• Metabolic and Cardiovascular: estrogen influences bone health, adiposity, circulating levels of lipids and blood clotting factors.

Uses

• Primary hypogonadism: estrogen therapy mimics puberty development
• Post-menopausal HRT: addresses changes related to menopause, osteoporosis, cardiovascular issues
• HRT has risks and rewards and must be considered for age, osteoporosis, cardiovascular diseases, breast or endometrial cancers.

Breast Cancer Risk

• Minimal if initiated post-menopause for the first seven years
• Should be initiated immediately after menopause for minimizing cancer risk.
• Women with pre-mature menopause may benefit from HRT after menopause.

Endometrial Cancer Risk

• Reduced by adding progesterone alongside estrogen alone.
• Given first 25 days of the month and progesterone the last 10 to 14 days for those with a full uterus.
• Estrogen alone is acceptable for patients who have undergone a hysterectomy.
• HRT dose should be the smallest amount to mitigate symptoms.

Adverse Effects

• Uterine bleeding - a common, but serious, symptom that may signal endometrial cancer
• Breast cancer: risk increases with prolonged therapy, but minimized with shortest therapy
• Endometrial cancer: Risk increases with dose and duration, but minimization is possible with progesterone addition
• Other conditions: nausea, breast tenderness, migraines, gallstones, HTN, estrogen-dependent cancers, undiagnosed vaginal bleeding, risk of thromboembolic disorders, liver disease, smoking are contraindications to initiating estrogen therapy.

Estrogen Inhibitors

• Tamoxifen: is a partial agonist at the estrogen receptor. Works by binding estrogen/receptor co-activators and reducing breast cancer risk in high risk patients.
• Tamoxifen is an anti-estrogenic agent in breast tissue but a mild estrogenic effect in the endometrium.

Other Inhibitors

• Letrozole and Exemestane are aromatase inhibitors
• Aromatase inhibitors reduce estrogen production by blocking aromatase, an enzyme that converts androgens to estrogen.

Ovulation Inducers (Clomiphene Citrate)

• Partial estrogen receptor agonist
• Inhibits estrogen actions
• Elevates LH and FSH levels
• Used for PCOS treatment
• Can cause ovarian enlargement
• Contraindicated in patients with enlarged ovaries.

PCOS Mechanism

• Genetic predisposition to excess ovarian androgen secretion
• Polycystic ovary, hirsutism, elevated testosterone and insulin levels, insulin resistance and hyperinsulinemia, anovulation
• Insulin resistance may be influenced by genetics and dietary factors