Hormones and The Menstrual Cycle

Endocrine System and Hormones

• Hormones are prescribed for various reasons including pregnancy prevention, menstrual disorders, and perimenopause/menopause.
• Contraception and Menopausal Hormone Therapy (MHT) are common uses in women, including vaginal atrophy postmenopause.

Gonadotropins (LH and FSH) Regulation

• LH and FSH regulate the growth, maturation of the ovarian graafian follicle and the ovarian production of estrogen and progesterone.
• Feedback regulation occurs among the pituitary, hypothalamus, and ovaries.
• LH and FSH secretion is pulsatile due to intermittent GnRH release.

Menstrual Cycle Hormonal Patterns

• LH and FSH levels fluctuate throughout the menstrual cycle, displaying distinct patterns during follicular and luteal phases.
• FSH stimulates follicle growth into an ovum, while LH stimulates estradiol production by follicles.
• Estrogen decreases FSH and LH release for most of the cycle but triggers an LH surge at midcycle, controlling gonadotropin (LH/FSH) pulse amplitude.
• Progesterone decreases GnRH release frequency and increases LH pulse amplitude during the luteal phase.

Estrogens and Progestins

• These regulate ovulation and the menstrual cycle, prepare the female reproductive tract for fertilization and implantation and influence metabolism and overall body functions.

Estrogen in Males

• Estrogen supports bone health and contributes to spermatogenesis, as well as affecting behavior and brain development.
• Estrogen deficiency delays skeletal maturation and epiphyseal closure, leading to prolonged linear growth.

Contraceptive Types and Considerations

• Combination oral contraceptives (COCs) contain both estrogen and progestin and prevent ovulation.
• Triphasic, biphasic, and monophasic pills offer offer a theoretical efficacy of 99%
• Progestin contributes to thick, cervical mucus to reduce sperm penetration

Adverse Effects of Contraceptives

• Combined oral contraceptives have cardiac risks like hypertension and venous thromboembolism and may increase potential cancers like Breast, hepatocellular, and cervical cancers
• Progestin-only pills (POPs) often cause irregular spotting and breakthrough bleeding, which is the most common reason women discontinue use.

Contraindications of Contraceptives

• Thromboembolic disease, cerebrovascular/coronary artery disease, known/suspected carcinoma/pregnancy, and abnormal vaginal bleeding
• Risk of cardiovascular side effects increases in women over 35 who smoke heavily while using estrogenous contraceptives.

Combined Oral Contraceptives

• Used to suppress gonadotropins, inhibit ovulation, reduce menstrual flow, and stabilize the endometrial lining.
• Side effects may include nausea, weight gain, and mood changes

Post-Coital Contraception

• Emergency contraception options include copper IUD, levonorgestrel, ulipristal, and mifepristone.
• Indicates failure of barrier devices or unprotected intercourse and is less effective than standard oral contraceptives.

Mifepristone (RU-486)

• Competitive antagonist at progesterone and glucocorticoid receptors, primarily used for medical abortion (≤ 70 days gestation) in combination with misoprostol as well as Cushing's syndrome
• Side effects includes vaginal bleeding and abdominal pain

Ulipristal Acetate (Ella)

• Selective progesterone receptor modulator (SPRM), used for emergency contraception up to 5 days post-intercourse and for uterine fibroids in some countries
• Clinical pearl is that it delays follicular rupture, may prevent implantation by altering endometrium.

Progestins - Key Actions

• Progestins bind to PR-A and PR-B receptors, regulating gene expression and suppressing LH surges to inhibit ovulation.
• They thicken cervical mucus and reduce endometrial proliferation.

Types and Clinical Uses of Progestins

• Pregnane derivatives (e.g., MPA) are closest to natural progesterone and used for MHT and contraception.
• Estrane derivatives (e.g., norethindrone) are common in oral contraceptives.
• Progestins for Acne, PCOS, and PMDD
• Spironolactone-derived progestins (e.g., drospirenone) have antiandrogenic effects.

Progestin: Administration route variations

• Oral tablet forms undergo significant first-pass metabolism, and synthetics have longer half-lives.
• MPA (Depo-Provera) is given via IM injection with long-acting q3 month administration.
• Levonorgestrel-releasing IUDs (Mirena, Skyla) provide slow release over years.

Depro-Provera uses (progestin only contraceptive)

-Effective within 24 hours if given during the first 5 days of menses as well as to manage endometriosis, amenorrhea and endometrial hyperplasia prevention

• Adverse effects of Depo-Proverso: wt gain, irregular bleeding, mood changes and Decreases bone mineral density

Mini pill (progestin only pill)

• Ideal for breastfeeding women & women with estrogen contradictions, strict adherence needed with a 3-hour window
• Subdermal etonogestrel-releasing rod implant can be effective for up to 3-5 years

Considerations for Prescribing Progestins

• Key considerations include age, reproductive goals, existing comorbidities, and the need for estrogen combination. Bone health and mental health should be monitored
• Fertility desires should be considered between fertility and contraception with implant options

HRT and Cardiovascular Risks

• HRT can be beneficial in younger women for heart disease but original WHI data suggested a harm.
• Low doses of progesterone is paired with estrogen when giving HRT
• Estrogen therapy is effective in managing vasomotor symptoms, preventing bone loss, and alleviating urogenital atrophy

SERMs (Selective Estrogen Receptor Modulators) - Mechanism

• Binds to estrogen receptors (ER) and act as agonists or antagonists depending on the target tissue

SERMs and Clinical Applications

• Tamoxifen serves as ER+ breast cancer treatment and prevention, Raloxifene Used for Bone issues, and Toremifene Used in Metastatic Breast Cancer

Estrogen Clinical Significance

• Makes cervical mucous watery/welcoming to sperm and enhances the contraceptive effect of progesterone

Medication induced hair growth treatment

First-line is COCs Spironolactone is anti-androgenic Finasteride reduces hair growth

Testoterone

• Testosterones are most commonly indicated for HSDD (hypoactive Sexual Desire Disorder) and increases sexual desire and arousal but is not FDA approved for woman
• Denusomab is for PM women who can' tolerate/ not tolarating bisphospinates but cannot be stopped abruptly

Bisphosphonates MOA

• Inhibit farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway & Induce osteoclast apoptosis
• ADME includes that you need to take it SITTING UP/ Administer following an overnight fast and at least 30 minutes before breakfast/Administered at least with full glass of water

Osteoporosis Therapy/ Vitamin D

• Start with lifestyle first step (weight bearing, exercises, fall prevention, ect)
• For all, adequate calcium (1000-1200 mg/day) and vitamin D (800-1000 IU/day)