FEMALE HORMONE PHYSIOLOGY









FEMALE HORMONES
Estradiol (E2)
  • Reproductive age
    • Primary hormone secreted by the follicle in the ovaries
    • 12 - 80 times more potent than estrone and estriol
    • Stimulates development of the female sex organs during puberty
    • Stimulates 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
Estrone (E1)
  • Reproductive age
    • 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
    • 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
    • Main pregnancy estrogen
    • Synthesized in the placenta
    • Has no significant role outside of pregnancy
  • Menopause
    • No significant role
Progesterone
  • Reproductive age
    • Produced by the corpus luteum in the ovaries
    • Causes the endometrium to become secretory, preparing it for ovum implantation
    • Produced by the placenta during the second and third trimesters
    • Progesterone levels measured 1 week prior to expected menses (cycle day 21) can be used to assess ovulation. Typically a level > 3 ng/ml indicates ovulation.
    • 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
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
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
    • Produced by the ovaries in small amounts
    • Aromatase 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 [1,2]
Anti-Müllerian hormone
  • Reproductive age
    • Anti-Müllerian hormone, also called Müllerian-inhibiting hormone, is a hormone produced by granulosa cells. Granulosa cells surround eggs in the ovaries 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. Women with low levels (< 1 ng/ml) often have a poor response to ovarian stimulation that is used for 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 [1,2]













  • 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%




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) which decreases the negative feedback of estradiol and increases GnRH release (see HPO axis above).
    • Increased GnRH release stimulates FSH release which in turn, stimulates ovarian follicular development
  • Dosing
    • Starting: 50 mg once daily for 5 days starting on the 5th day of the cycle
    • Dose may be increased to 100 mg/day in subsequent cycles
    • In studies, doses up to 150 mg/day have been used
    • For women with no recent menstruation, therapy may be started at any time
    • 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
    • May cause visual blurring or other visual symptoms such as spots or flashes
    • May cause abdominal bloating, breast pain, and hot flashes
    • Ovarian hyperstimulation syndrome may occur. Symptoms include abdominal or pelvic pain, weight gain, discomfort, and distention.
    • Increases chance of multiple pregnancies (6 - 9% depending on the study and patient population)
    • Use lower dose in PCOS
Letrozole (Femara®)
  • Mechanism
    • In the ovaries, the aromatase enzyme converts testosterone and androstenedione to estradiol
    • Letrozole inhibits aromatase and decreases estradiol levels
    • With decreasing estradiol levels, negative feedback on the pituitary is diminished, and FSH production is increased (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.
    • May cause fatigue, dizziness, and somnolence
    • May cause abdominal bloating, breast pain, and hot flashes
    • Ovarian hyperstimulation syndrome may occur. Symptoms include abdominal or pelvic pain, weight gain, discomfort, and distention.
    • Increases chance of multiple pregnancies (3 - 13% depending on the study and patient population)
Gonadotropins (Gonal-f®, Menopur®)
  • Mechanism
    • Gonadotropins (FSH and LH) are available in several injectable preparations
    • FSH stimulates follicular development (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 response is observed, hCG is injected to stimulate ovulation
    • Injections are very expensive
  • Other
    • May cause 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 32% depending on the study and patient population)



Infertility studies

FSH vs Clomiphene ± Intrauterine Insemination (IUI) in Unexplained Infertility, Lancet (2018) [PubMed abstract]
  • Design: Randomized, controlled trial (N=666, length = up to 6 cycles) in women who had used clomiphene for 6 cycles and not conceived
  • Treatment: FSH + HCG vs Clomiphene 50 - 150 mg/day. Both groups were also randomly assigned to IUI or regular intercourse.
  • Primary outcome: Conception leading to livebirth within 8 months after randomisation, defined as any baby born alive with a gestational age beyond 24 weeks
  • Results:
    • Livebirth: FSH/HCG + IUI - 54%, FSH/HCG + intercourse - 48%, Clomiphene + IUI - 44%, Clomiphene + intercourse - 39% (FSH/HCG vs Clomiphene p=0.0124 | IUI vs intercourse p=0.12)
  • Findings: In women with normogonadotropic anovulation and clomiphene citrate failure, a switch of treatment to gonadotropins increased the chance of livebirth over treatment with clomiphene citrate; there was no evidence that addition of intrauterine insemination does so.
Clomiphene or Letrozole + Intrauterine Insemination (IUI) vs Expectant Management for Unexplained Infertility, Lancet (2018) [PubMed abstract]
  • Design: Randomized, controlled trial (N=201, length = up to 3 cycles) in women with unexplained infertility
  • Treatment: Clomiphene 50 - 150 mg/day or letrozole 2.5 - 7.5 mg/day for 5 days + IUI vs Expectant management (no intervention)
  • Primary outcome: Cumulative live birth rate in the intention-to-treat population
  • Results:
    • Live birth: Ovarian stimulation + IUI - 31%, Expectant management - 9% (p=0.0003)
    • Clinical pregnancy: Ovarian stimulation + IUI - 37%, Expectant management - 11% (p<0.0001)
    • Multiple pregnancies (out of live births): Ovarian stimulation + IUI - 6%, Expectant management - 0%
  • Findings: IUI with ovarian stimulation is a safe and effective treatment for women with unexplained infertility and an unfavourable prognosis for natural conception
Letrozole vs Clomid vs Gonadotropin (Menopur) for Unexplained Infertility, NEJM (2015) [PubMed abstract]
  • Design: Randomized, controlled trial (N=900, length = up to 4 cycles) in women with unexplained infertility
  • Treatment: Letrozole 2.5 - 7.5 mg/day for 5 days vs Clomiphene 100 mg/day for 5 days vs Gonadotropin (Menopur) daily until hCG | All groups received 10,000 IU of hCG upon follicle development | All groups received intrauterine insemination
  • Primary outcome: Rate of multiple gestations among women with clinical pregnancies
  • Results:
    • Multiple gestations (among clinical pregnancies): Gonadotropin - 32%, Clomiphene - 9%, Letrozole - 13%
    • Clinical pregnancy: Gonadotropin - 36%, Clomiphene - 28%, Letrozole - 22%
    • Live births (among all women): Gonadotropin - 32%, Clomiphene - 23%, Letrozole - 19%
  • Findings: In women with unexplained infertility, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomiphene.
Clomiphene vs FSH vs Immediate IVF for Unexplained Infertility, Fertil Steril (2014) [PubMed abstract]
  • Design: Randomized, controlled trial (N=154, length = up to 2 cycles) in women with > 6 months of unexplained infertility
  • Treatment: Clomiphene 100 mg/day for 5 days vs FSH 300 IU/day for 3 days vs Immediate IVF | Clomiphene group received 10,000 IU of hCG if necessary | FSH groups received 10,000 IU of hCG upon follicle development | Clomiphene/FSH groups received intrauterine insemination
  • Primary outcome: Proportion with a clinically recognized pregnancy, number of treatment cycles, and time to conception after two treatment cycles and at the end of treatment.
  • Results:
    • Clinical pregnancy: Clomiphene - 22%, FSH - 17%, IVF - 49%
    • Live births: Clomiphene - 16%, FSH - 14%, IVF - 31%
  • Findings: A randomized controlled trial in older women with unexplained infertility to compare treatment initiated with two cycles of controlled ovarian hyperstimulation/IUI versus immediate IVF demonstrated superior pregnancy rates with fewer treatment cycles in the immediate IVF group.
Birth Outcomes in Medically Assisted Reproduction vs Natural Reproduction, Lancet (2019) [PubMed abstract]
  • Design: Registry cohort study (N=65,723, length = 5 years) in households with at least one child aged 0 - 14 years
  • Exposure: Medically assisted reproduction (ovulation induction, artificial insemination, IVF, and/or ICSI with fresh or frozen embryo transfers) vs Natural reproduction
  • Primary outcome: Birthweight, gestational age, risk of low birthweight, and risk of preterm birth
  • Results:
    • Birthweight (grams): Medically assisted - 3286, Natural - 3551 (p<0.0001)
    • Low birthweight: Medically assisted - 13%, Natural - 3% (p<0.0001)
    • Gestational age (days): Medically assisted - 271, Natural - 278 (p<0.0001)
    • Preterm birth: Medically assisted - 15%, Natural - 5% (p<0.0001)
  • Findings: Children conceived by medically assisted reproduction face an elevated risk of adverse birth outcomes. However, our results indicate that this increased risk is largely attributable to factors other than the medically assisted reproduction treatment itself



Infertility in PCOS

Letrozole vs Clomiphene for Infertility in PCOS, NEJM (2014) [PubMed abstract]
  • Design: Randomized controlled trial (N=750, length = up to 5 cycles) in infertile women with PCOS
  • Treatment: Letrozole 2.5 - 7.5 mg/day for 5 days vs Clomiphene 50 - 150 mg/day for 5 days | Both drugs were started on cycle day 3
  • Primary outcome: Live births during the treatment period
  • Results:
    • Live births: Letrozole - 27.5%, Clomiphene - 19.1% (p=0.007)
    • Twin live births: Letrozole - 3.4%, Clomiphene - 7.4% (p=0.32)
  • Findings: As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome.
Clomiphene vs Metformin vs Clomiphene + Metformin for Infertility in PCOS, NEJM (2007) [PubMed abstract]
  • Design: Randomized controlled trial (N=626, length = up to 6 months) in infertile women with PCOS
  • Exposure: Metformin 1000 mg twice daily vs Clomiphene 50 - 150 mg/day for 5 days beginning on day 3 of menses vs Both treatments
  • Primary outcome: Rate of live births
  • Results:
    • Live births: Clomiphene - 23%, Metformin 7%, Clomiphene + Metformin - 27% (p<0.001 for metformin vs both clomiphene and combination therapy | p=0.31 for clomiphene vs combination therapy)
    • Multiple pregnancies (among all pregnancies): Clomiphene - 6%, Metformin 0%, Clomiphene + Metformin - 3%
  • Findings: Clomiphene is superior to metformin in achieving live birth in infertile women with the polycystic ovary syndrome, although multiple birth is a complication.



IVF studies

Transfer of Frozen vs Fresh Embryos in IVF, NEJM (2018) [PubMed abstract]
  • Design: Randomized controlled trial (N=2157, length = 1 transfer) in ovulatory women with infertility due to tubal factors, male factors, or both
  • Treatment: Transfer of fresh embryos vs frozen embryos
  • Primary outcome: Live birth (≥ 28 weeks gestation) after the first transfer
  • Results:
    • Live births: Frozen - 49%, Fresh - 50% (p=0.50)
  • Findings: The live-birth rate did not differ significantly between fresh-embryo transfer and frozen-embryo transfer among ovulatory women with infertility, but frozen-embryo transfer resulted in a lower risk of the ovarian hyperstimulation syndrome.
Transfer of Frozen vs Fresh Embryos in IVF in Women Without PCOS, NEJM (2018) [PubMed abstract]
  • Design: Randomized controlled trial (N=782, length = 1 transfer) in infertile women without PCOS
  • Treatment: Transfer of fresh embryos vs frozen embryos
  • Primary outcome: Pregnancy after first transfer defined as pregnancy with a detectable heart rate after 12 weeks of gestation
  • Results:
    • Live births: Frozen - 36%, Fresh - 35% (p=0.65)
  • Findings: Among infertile women without the polycystic ovary syndrome who were undergoing IVF, the transfer of frozen embryos did not result in significantly higher rates of ongoing pregnancy or live birth than the transfer of fresh embryos.
Transfer of Frozen vs Fresh Single Blastocyst in IVF, Lancet (2019) [PubMed abstract]
  • Design: Randomized controlled trial (N=1650, length = 1 transfer) in women with regular menstrual cycles undergoing their first cycle of IVF
  • Treatment: Single fresh blastocyst transfer vs Single frozen blastocyst transfer
  • Primary outcome: Singleton livebirth rate
  • Results:
    • Live births: Frozen - 50%, Fresh - 40% (p<0.0001)
  • Findings: Frozen single blastocyst transfer resulted in a higher singleton livebirth rate than did fresh single blastocyst transfer in ovulatory women with good prognosis. The increased risk of pre-eclampsia after frozen blastocyst transfer warrants further studies.
Association of IVF With Childhood Cancer in the United States, JAMA Pediatrics (2019) [PubMed abstract]
  • Design: Retrospective cohort study (N=2,542,533, length = 10 years) in children born in the United States
  • Exposure: Conceived via IVF vs Not conceived via IVF
  • Primary outcome: Cancer diagnosed in the first decade of life
  • Results:
    • Cancer rate (per 1,000,000 person-years): IVF - 252, Non-IVF - 193 (HR 1.17; 95%CI [1.00-1.36])
  • Findings: This study found a small association of IVF with overall cancers of early childhood, but it did observe an increased rate of embryonal cancers, particularly hepatic tumors, that could not be attributed to IVF rather than to underlying infertility. Continued follow-up for cancer occurrence among children conceived via IVF is warranted.



Other studies

Endometrial Scratching vs None before IVF, NEJM (2019) [PubMed abstract]
  • Design: Randomized controlled trial (N=1364, length = 1 transfer) in women planning IVF with their own oocytes
  • Treatment: Endometrial scratching vs No endometrial scratching
  • Primary outcome: Live birth
  • Results:
    • Live births: Endometrial scratching - 26.1%, No endometrial scratching - 26.1%
  • Findings: Endometrial scratching did not result in a higher rate of live birth than no intervention among women undergoing IVF
Physiological, hyaluronan-selected ICSI vs Standard ICSI for infertility treatment, Lancet (2019) [PubMed abstract]
  • Design: Randomized controlled trial (N=2772, length = 1 transfer of 1 - 3 fresh embryos) in women undergoing IVF with embryos formed from intracytoplasmic sperm injection (ICSI)
  • Treatment: Hyaluronan-based sperm selection for ICSI (so-called physiological ICSI [PICSI]) vs standard ICSI
  • Primary outcome: Full-term (≥37 weeks’ gestational age) livebirth
  • Results:
    • Live births: Physiological ICSI (PICSI) - 27.4%, Standard ICSI - 25.2% (p=0.18)
  • Findings: Compared with ICSI, PICSI does not significantly improve term livebirth rates. The wider use of PICSI, therefore, is not recommended at present.
Association Between Biomarkers of Ovarian Reserve and Infertility Among Older Women of Reproductive Age, JAMA (2017) [PubMed abstract]
  • Design: Prospective cohort study (N=750, length = up to 12 cycles) in women aged 30 to 44 years without a history of infertility who had been trying to conceive for ≤ 3 months
  • Measured variables: Early-follicular-phase serum level of Antimüllerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B and urinary level of FSH
  • Primary outcome: Cumulative probability of conception by 6 and 12 cycles of attempt and relative fecundability (probability of conception in a given menstrual cycle). Conception was defined as a positive pregnancy test result.
  • Results:
    • Conception during study (% of women) by Antimüllerian hormone level
      • < 0.7 ng/ml (N=84): 63%
      • 0.7 - 8.4 ng/ml (N=579): 66%
      • ≥ 8.5 ng/ml (N=74): 59%
  • Findings: Among women aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, biomarkers indicating diminished ovarian reserve compared with normal ovarian reserve were not associated with reduced fertility. These findings do not support the use of urinary or blood follicle-stimulating hormone tests or antimüllerian hormone levels to assess natural fertility for women with these characteristics.



  • 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 ?