FEMALE HORMONE PHYSIOLOGY









  • References [1,2,10]
FEMALE HORMONES
Estradiol (E2)
  • Reproductive age
    • Estradiol is the primary hormone secreted by the follicle in the ovaries, and it is 12 - 80 times more potent than estrone and estriol
    • Estradiol stimulates development of the female sex organs during puberty, and it causes thickening of the endometrium during the menstrual cycle
    • Normal range: 12.5 - 498 pg/ml depending on the phase of the menstrual cycle
  • Menopause
    • Ovarian estradiol production ceases
    • A small amount is produced by the conversion of adrenal steroids in peripheral fat tissue
    • Normal range: 0 - 55 pg/ml depending on the length of menopause
  • Infertility
    • As women age, ovarian follicles gradually decline. Follicle loss leads to lower estradiol levels and reduced negative feedback on the pituitary. (see HPO axis). FSH levels rise, and this causes elevated estradiol levels in the early follicular phase (see menstrual cycle).
    • To test for ovarian reserve, an estradiol level and an FSH can be checked on Day 3 of the cycle. FSH levels >10 - 15 mIU/ml and estradiol levels >60 - 80 pg/ml suggest low ovarian reserve. See infertility evaluation below.
Estrone (E1)
  • Reproductive age
    • Estrone is not as potent or abundant as estradiol
    • Normal range: 37 - 229 pg/ml depending on the phase of the menstrual cycle
  • Menopause
    • After estradiol levels fall, estrone becomes the predominant estrogen. It is primarily formed from peripheral aromatization of androstenedione in the adrenal gland.
    • Normal range: 14 - 103 pg/ml depending on the length of menopause
Estriol (E3)
  • Reproductive age
    • Estriol is synthesized in the placenta, and it is the main estrogen of pregnancy. It has no significant role outside of pregnancy.
  • Menopause
    • No significant role
Progesterone
  • Reproductive age
    • Progesterone is produced by the corpus luteum in the ovaries. It causes the endometrium to become secretory, preparing it for ovum implantation.
    • In pregnancy, it is produced by the placenta during the second and third trimesters
    • Normal range: 0.2 - 27 ng/ml depending on the phase of the menstrual cycle
  • Menopause
    • Ovarian progesterone production stops
    • Normal range: 0.1 - 0.8 ng/ml
  • Infertility
    • Progesterone levels measured 1 week prior to expected menses (cycle day 21) can be used to detect ovulation. A level ≥ 3 ng/ml means that ovulation likely occurred. See infertility evaluation below.
Follicle-stimulating hormone (FSH)
  • Reproductive age
    • FSH is released from the anterior pituitary in response to GnRH. FSH stimulates follicles in the ovary to mature.
    • Normal range: 3.5 - 21.5 mIU/ml depending on the phase of the menstrual cycle
  • Menopause
    • Loss of negative feedback from estrogen leads to high levels
    • Normal range: 25.8 - 135 mIU/ml
  • Infertility
    • As women age, ovarian follicles gradually decline. Follicle loss leads to lower estradiol levels and reduced negative feedback on the pituitary. (see HPO axis). FSH levels rise, and this causes elevated estradiol levels in the early follicular phase (see menstrual cycle).
    • To test for ovarian reserve, an estradiol level and an FSH can be checked on Day 3 of the cycle. FSH levels >10 - 15 mIU/ml and estradiol levels >60 - 80 pg/ml suggest low ovarian reserve. See infertility evaluation below.
Luteinizing hormone (LH)
  • Reproductive age
    • LH is released from the anterior pituitary in response to GnRH
    • The LH surge in the middle of the menstrual cycle stimulates ovulation
    • LH maintains the corpus luteum and stimulates steroid production
    • Normal range: 2.4 - 95.6 mIU/ml depending on the phase of the menstrual cycle
  • Menopause
    • Loss of negative feedback from estrogen leads to higher levels
    • Normal range: 7.7 - 58.5 mIU/ml
Testosterone
  • Reproductive age
    • Testosterone is produced by the ovaries in small amounts. The aromatase enzyme converts testosterone to estradiol in the ovaries.
    • Normal range: 8 - 48 ng/dl
  • Menopause
    • Ovaries continue to produce testosterone
    • Normal range: 3 - 41 ng/dl
Dehydroepiandrosterone (DHEA)
  • Reproductive age
    • DHEA is a mild androgen produced by the adrenal cortex
    • In peripheral tissues, DHEA can be converted into estradiol or testosterone
    • DHEA levels peak around age 30 and then gradually decline
    • DHEA-S is an active metabolite of DHEA that has a much longer half-life. DHEA-S is present in concentrations 300 - 500 times that of DHEA. DHEA levels have a diurnal variation where DHEA-S only has minimal diurnal variation. Because of this, DHEA-S is often the preferred lab for measuring DHEA activity.
    • DHEA-S levels are typically measured to screen for adrenal hyperfunction in women with virilization
    • Normal range: DHEA-S levels vary by age with a peak range of 84 - 378 mcg/dl around age 30
  • Menopause
    • DHEA production continues to decline with levels falling to 10 - 25% of their peak value by age 70 - 80 years
Anti-Müllerian hormone
  • Reproductive age / Fertility
    • Anti-Müllerian hormone, also called Müllerian-inhibiting hormone, is a hormone produced by granulosa cells in the ovary. Granulosa cells surround eggs and support their development. Anti-Müllerian hormone inhibits follicle recruitment in resting eggs so that a dominant follicle can develop. As the number of eggs in the ovary diminishes, levels of anti-Müllerian hormone decrease.
    • Anti-Müllerian hormone is often used to measure ovarian reserve in women who are trying to conceive. Levels < 1.66 ng/ml are indicative of low ovarian reserve, and levels < 1 ng/ml portend a poor response to ovarian stimulation used in vitro fertilization (IVF).
    • Despite being a marker of ovarian reserve, anti-Müllerian hormone has not been shown to be a good predictor of fertility. See biomarkers of ovarian reserve and infertility below.
  • Normal ranges
    • 20 - 30 years old: median values range from 4.2 - 4.7 ng/ml
    • 30 - 40 years old: median values range from 1.69 - 3.0 ng/ml
    • 40 - 50 years old: median values range from <0.03 - 0.58 ng/ml
  • Menopause
    • Levels are undetectable













  • Reference [8]
% of women achieving menopause within 5 years based on AMH levels
AMH levels
Age range Undetectable 0.09 - 1.9 ng/ml ≥ 2.0 ng/ml
40 - 44 years (N=192) 40% 5% 0%
45 - 49 years (N=121) 60% 23% 0%

  • FSH levels were drawn on days 1- 10 of the menstrual cycle in women with normal menstration
  • Reference [8]
% of women achieving menopause within 5 years based on FSH levels
FSH levels
Age range 0 - 5.39 IU/L 5.4 - 13 IU/L > 13 IU/L
40 - 44 years (N=192) 6% 6% 22%
45 - 49 years (N=121) 31% 23% 46%





  • Reference [10]
Steps to evaluating infertility
Step 1 - determine if patient is ovulating
  • A regular menstrual cycle (every 21 - 35 days) with premenstrual symptoms (e.g. breast tenderness, fluid retention) indicates ovulation
  • Irregular menses (cycles < 21 days or > 35 days), amenorrhea, and abnormal uterine bleeding are suggestive of anovulation
  • If ovulation is unclear from patient history, check a serum progesterone on day 21 of the menstrual cycle. A level > 3 ng/ml means ovulation likely occurred.
Step 2 - order testing based on ovulation status

  • No evidence of ovulation
    • Check TSH, prolactin, FSH, and LH
    • In women with signs of PCOS (e.g. acne, hirsutism, male-pattern hair loss), also order free and total testosterone, DHEA-S, and 17-hydroxyprogesterone (17-OHP)

  • Evidence of ovulation
    • Evaluate ovarian reserve with one or more of the following tests:
      • Anti-Müllerian hormone test - level < 1.66 ng/ml suggests low ovarian reserve
      • FSH and estradiol on Day 3 of cycle - FSH >10 - 15 mIU/ml and estradiol >60 - 80 pg/ml suggests low ovarian reserve
      • Pelvic ultrasound with antral follicle count - antral follicles are resting follicles 2 - 10 mm in diameter that can be seen on an ultrasound. Their sum is directly proportional to the number of eggs remaining in the ovary. A count of < 4 follicles (both ovaries combined) suggests low ovarian reserve.
    • Test partner semen
    • Further testing when indicated
      • Pelvic ultrasound - evaluate for uterine abnormalities
      • Hysterosalpingogram - evaluate for tubal patency
Step 3 - considerations based on results
  • Abnormal TSH - hypo- or hyperthyroidism should be treated to see if ovulation returns
  • Elevated prolactin - prolactinoma should be treated (surgery or dopamine agonists) to see if ovulation returns
  • PCOS - in obese women, weight loss of ≥ 15% can cause ovulation to return. Metformin may be beneficial for women with type two diabetes or glucose intolerance. Clomiphene is the recommended first-line treatment for infertility in PCOS.
  • Low ovarian reserve - referral to infertility specialist for ovarian stimulation, IVF, etc.
  • Hypogonadotropic hypogonadism (low FSH and LH) - referral to infertility specialist. Pulsatile GnRH therapy can restore ovulation in many women. Exogenous FSH and LH may also be used.
  • Abnormal semen - referral to urologist for further evaluation/treatment
  • Uterine or tubal abnormalities - referral to infertility specialist for further evaluation/treatment

  • Values are based on samples from men who had fathered a pregnancy in the previous year and taken after 2 to 7 days of abstinence. Cutoff values are 5th percentile.
  • Abnormal results should be confirmed on repeat analysis at least 1 month later
  • Reference [10]
Normal semen parameters
Measure Normal value
Sperm concentration
  • ≥ 15 million sperm/ml
Motility
  • ≥ 40% forward progression
Total motile sperm count (TMC)
  • TMC = (sperm volume) X (sperm concentration) X (% motile)
  • TMC < 20 million is associated with a lower probability of fathering a child
Sperm morphology
  • ≥ 4% normal forms
White blood cell count
  • < 1 million/ml

  • Reference [Manufacturer's PI, 10]
Infertility drugs
Clomiphene (Clomid®)
  • Mechanism
    • Clomiphene is a selective estrogen receptor modulator (SERM). See SERM activity table for more.
    • Clomiphene blocks estrogen receptors in the hypothalamus (and possibly the pituitary), and this inhibits negative feedback from estradiol. GnRH release is increased, leading to higher FSH levels (see HPO axis above). FSH stimulates follicular development.
  • Dosing
    • Starting: 50 mg once daily for 5 days starting on the 5th day of the cycle. For women with no recent menstruation, therapy may be started at any time.
    • Dose may be increased to 100 mg/day in subsequent cycles. In studies, doses up to 150 mg/day have been used.
    • Only 3 cycles are recommended, but it has been used for up to 6 cycles in some studies
    • Dosage form: 50 mg tablet
    • Generic: - YES / less than $50 for 30 tablets
  • Other
    • Side effects include headache (34%), hot flashes (33%), irritability (21%), fatigue (14%), dizziness (7%), thin endometrium (15% - 50%), and visual blurring or other visual symptoms such as spots or flashes (2%).
    • Ovarian hyperstimulation syndrome may occur. Symptoms include abdominal or pelvic pain, weight gain, discomfort, and distention.
    • Increases chance of multiple pregnancies (up to 12.5% in some studies)
    • Use lower dose in PCOS
Letrozole (Femara®)
  • Mechanism
    • In the ovaries, the aromatase enzyme converts testosterone and androstenedione to estradiol. Letrozole inhibits aromatase and blocks the production of estradiol. With decreasing estradiol levels, negative feedback on the pituitary is diminished, and FSH levels rise (see HPO axis above). FSH stimulates ovarian follicular development.
  • Dosing
    • Dosing: 2.5 - 5 mg once daily for 5 days starting on Day 3 - 5 of the menstrual cycle
    • Doses up to 7.5 mg/day have been used in studies
    • Has been used for up to 5 cycles in studies
    • Dosage form: 2.5 mg tablet
    • Generic: - YES / less than $50 for 30 tablets
  • Other
    • Letrozole is FDA-approved as an adjuvant treatment in breast cancer. Use in infertility is off-label.
    • Side effects include headache (41%), fatigue (21.7%), hot flashes (20.3%), irritability (18%), dizziness (12.3%), abdominal bloating, and breast pain
    • Ovarian hyperstimulation syndrome may occur. Symptoms include abdominal or pelvic pain, weight gain, discomfort, and distention.
    • Increases chance of multiple pregnancies (up to 14.3% in some studies)
Gonadotropins (Gonal-f®, Menopur®)
  • Mechanism
    • Gonadotropins (FSH and LH) are available in several injectable preparations
    • FSH stimulates follicular development, and LH maintains the corpus luteum (see HPO axis above)
    • Gonal-f is FSH made from recombinant DNA
    • Menopur is 1:1 mixture of FSH and LH. Menopur is extracted from the urine of postmenopausal women.
  • Dosing
    • Gonadotropin is injected daily starting on Day 3 - 5 of the menstrual cycle
    • Ovarian response is monitored by ultrasound
    • Once appropriate follicular development is observed, hCG is injected to stimulate ovulation
    • Injections are very expensive
  • Other
    • May cause abdominal bloating (27 - 34%), injection site reactions (10%), and breast pain
    • Ovarian hyperstimulation syndrome may occur. Symptoms include abdominal or pelvic pain, weight gain, discomfort, and distention.
    • Increases chance of multiple pregnancies (up to 36% in some studies)




























  • References PMID 25423325, PMID 25210448, PMID 10874566
SERM ACTIVITY TABLE
SERM Product Endometrium Vagina Breast Bone
formation
Hypothalamus
Bazedoxifene Duavee® Neutral to
Antagonist
No data Neutral to
Antagonist
Agonist ?
Clomiphene Clomid® Antagonist ? ? Agonist Antagonist
Ospemifene Osphena® Neutral to
Partial agonist
Agonist Antagonist Agonist ?
Raloxifene Evista® Neutral to
Partial agonist
Neutral Antagonist Agonist ?
Tamoxifen Nolvadex® Neutral to
Agonist
Agonist Antagonist Agonist ?