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 produced by the placenta, and it is the primary estrogen of pregnancy. It has no significant role outside of pregnancy. Menopause No significant role
Progesterone Reproductive age Progesterone is released 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 Estrogen loss reduces negative feedback in the pituitary and hypothalamus, and FSH levels rise 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 Estrogen loss reduces negative feedback in the pituitary and hypothalamus, and LH levels rise Normal range: 7.7 - 58.5 mIU/ml
Testosterone Reproductive age Testosterone is produced by the ovaries in small amounts. In the ovaries, aromatase converts testosterone to estradiol. 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 produced by ovarian granulosa cells, which 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

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• Phases
• Menses (days 0 - 5) - menses occurs during days 0 - 5 of the typical 28-day menstrual cycle. As the corpus luteum regresses, it stops secreting progesterone and estrogen. This causes the endometrium to necrose and slough off.
• Follicular phase (days 1 - 13) - the follicular phase is the first 13 days of a menstrual cycle, where FSH released by the pituitary stimulates the development of a mature follicle. A developing follicle secretes estradiol up to ovulation, at which point it enters the luteal phase.
• Ovulation (days 13 - 14) - ovulation is the release of an egg from a mature follicle, and it typically occurs on days 13 or 14 of a cycle.
• Luteal phase (days 14 - 28) - the final 14 - 28 days of a cycle are the luteal phase. The evacuated follicle becomes the corpus luteum, which releases progesterone and estrogen. Progesterone causes the endometrium to become secretory, preparing it for ovum implantation. Luteinizing hormone stimulates the corpus luteum until it regresses around days 24 - 26, at which point hormone levels plunge, and the endometrium is no longer supported.

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• Overview
• PCOS is characterized by polycystic ovaries, irregular menses, and hyperandrogenism. Obesity is present in 50 - 80% of affected individuals, insulin resistance in 35%, and type 2 diabetes in 8 - 10%. It is a common condition, prevalent in 10% of women, and likely underdiagnosed. The pathology is not completely understood but involves abnormalities in ovarian follicular development and steroidogenesis that lead to excessive ovarian androgen production and ovulatory dysfunction. [11,12]

• Recommendations are from the International Evidence-based Guideline for the assessment and management of PCOS 2023
• Reference [11]

2023 PCOS Diagnostic Criteria
STEP 1 - Assess if the following two criteria are met: 1. Irregular cycles, defined as any of the following: Greater than 1 to less than 3 years post menarche: cycle length < 21 or > 45 days Greater than 3 years post menarche to perimenopause: cycle length < 21 or > 35 days or < 8 cycles/year Greater than 1 year post menarche and cycle length greater than 90 days for any one cycle Primary amenorrhea by age 15 or > 3 years post thelarche (breast development) 2. Hyperandrogenism Hyperandrogenism may be clinical or biochemical. Biochemical hyperandrogenism is elevated serum testosterone levels. Clinical hyperandrogenism is defined as the following: Adults: acne, female pattern hair loss and hirsutism Adolescents: severe acne and hirsutism If both criteria are met, proceed to Step 2. If only one of the criteria is met, proceed to Step 3
STEP 2 - Both criteria are met Check the following to rule out other causes: TSH (thyroid disorders) Prolactin (hyperprolactinemia) 17-hydroxy progesterone (non-classic congenital adrenal hyperplasia) If clinically indicated, also consider the following: FSH and LH (hypogonadotropic hypogonadism) Cortisol (Cushing's disease) Androgen-producing tumors (rare) If both criteria are met and other causes are ruled out, PCOS is diagnosed
STEP 3 - Only one criterion is met Adolescents: No further workup is recommended. Patient should be considered at risk and reassessed later. Adults: Check ultrasound OR Anti-Mullerian hormone (AMH) level Ultrasound: If ultrasound shows polycystic ovarian morphology (follicle number per ovary of ≥ 20 and/or an ovarian volume ≥ 10 ml on either ovary, avoiding corpora lutea, cysts, or dominant follicles), rule out other causes (Step 2) and diagnose PCOS Anti-Mullerian hormone (AMH): If AMH level is elevated, rule out other causes (Step 2) and diagnose PCOS To avoid overdiagnosis, only ultrasound or AMH levels should be checked, not both

• Recommendations are from the International Evidence-based Guideline for the assessment and management of PCOS 2023
• Reference [11,13]

2023 PCOS Treatment Recommendations
First-line therapy Overweight patients - diet and exercise to obtain a healthy weight Combined oral contraceptive pills (COCP) All COCP are considered equally effective for treating PCOS Use the lowest effective estrogen dose (20 - 30 mcg) Progestin-only oral contraceptives may be considered for endometrial protection
Second-line therapy One of the following: Metformin Most useful when BMI is ≥ 25 and in high-risk ethnic groups Consider starting dose of 500 mg once daily and titrate at intervals of 1 - 2 weeks. Maximum dose is 2500 mg/day in adults and 2000 mg/day in adolescents. COCP + Metformin COCP treats hirsutism and irregular menstrual cycles, while metformin may help with metabolic issues In adults with a BMI ≤ 30, combination therapy offers little benefit over each therapy alone COCP + Anti-androgen Anti-androgen therapy may be indicated for hirsutism that does not respond to at least six months of a COCP and/or cosmetic therapy. Women of childbearing potential should be warned that anti-androgens may cause virilization of the male fetus. Anti-androgens include the following: Spironolactone - doses of 25 - 100 mg/day appear to be safe and effective Finasteride - doses of 0.5 - 5 mg/day have been used in studies Flutamide - 250 mg twice daily was used in one study [PMID 14725687]
Infertility in PCOS First-line: Letrozole Second-line: Gonadotropins Third-line: IVF

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• Overview
• Menopause occurs when ovarian follicles are depleted, and the production of estrogen and progesterone ceases
• Twelve consecutive months without menses is the definition used to mark the beginning of menopause. The median age of the final menstrual period is 52.5 years. Prior to this, women typically experience years of menstrual irregularities. [9]

• Symptoms
• Amenorrhea
• Hot flushes defined as episodic flushing and warmth of the skin often accompanied by sweating
• Vaginal dryness, burning, and irritation
• Sexual symptoms of diminished lubrication and pain
• Urinary urgency, dysuria, and recurrent urinary tract infections
• Irritability and anxiety
• Fatigue and weakness
• Decreased calcification of the bones (osteoporosis)

• Predicting menopause onset
• Menstrual patterns and biomarkers of ovarian reserve can be used to predict the onset of menopause, although neither one is precise
• In general, women who begin menopause at a younger age have a longer transition period and more symptoms than women who start at an older age

• Menstrual patterns
• Early menopause transition - marked by irregularities of ≥ 7 days in the intermenstrual cycle in women with previously normal cycles. This occurs at a median age of 47 years.
• Late menopause transition - amenorrhea for > 60 days, after which 95% of women will go on to have their final menstrual period within the next 4 years. The median age for the late menopause transition is 49 years.
• Menopause - marked by no menses for 12 consecutive months. The median age for the last menstrual period is 52.5 years, and most women go through menopause between the ages of 47 and 54 years. [9]

• Biomarkers of ovarian reserve
• FSH and Anti-Müllerian hormone (AMH) can both be used to predict menopause onset
• FSH levels increase as ovarian reserve decreases. Ideally, FSH levels should be drawn within the first 5 days of menses when they are at their highest. AMH levels fall as ovarian reserve decreases.
• Results from a study that measured AMH and FSH levels in 313 women before following them longitudinally for the onset of menopause are presented in the tables below

• 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%

• Treatment
• See menopause treatment guidelines and female hormone medications

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• Overview
• Infertility is defined as a failure to achieve pregnancy after 12 months of regular unprotected intercourse. In the U.S., about 8.8% of women aged 15 - 49 years are affected.
• The recommendations below provide a straightforward approach to initiating an infertility evaluation [10]

• 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 See semen parameters below for more 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

• 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), inhibiting negative feedback from estradiol. GnRH release is increased, leading to higher FSH levels that stimulate follicular development (see HPO axis above). 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, stimulating follicular development (see HPO axis above). 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)

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• RCT
  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.

• RCT
  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

• RCT
  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.

• RCT
  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.

• OBS
  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

• OBS
  Association Between Fertility Treatment and Cancer Risk in Children, JAMA (2019) [PubMed abstract]
• Design: Registry cohort study (N=1,085,172 | length = 11.3 years) in Danish children born between 1996 and 2012
• Exposure: Maternal fertility treatment including the use of fertility drugs (clomiphene, gonadotropins, gonadotropin-releasing hormone analogs, human chorionic gonadotropin, progesterone, and estrogen) and assisted reproductive technology (in vitro fertilization, intracytoplasmic sperm injection, and frozen embryo transfer) vs None
• Primary outcome: Hazard ratios and incidence rate differences for childhood cancer
• Results:
• Only frozen embryo transfer showed a significantly higher incidence of cancer compared to no treatment. (Incidence rate difference, 26.9 cases/100000 children, 95%CI[2.8 - 51.0])
• Findings: Among children born in Denmark, the use of frozen embryo transfer, compared with children born to fertile women, was associated with a small but statistically significant increased risk of childhood cancer; this association was not found for the use of other types of fertility treatment examined.

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• RCT
  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.

• RCT
  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.

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• OBS
  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.

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• 1 - LabCorp® website
• 2 - CPL® website
• 3 - PMID 17125587 NEJM Menopause review
• 4 - Clomiphene PI
• 5 - PMID 17287476 - clomiphene and metformin in PCOS
• 6 - PMID 26398071 - clomiphene vs letrozole vs gonadotropin
• 7 - PMID 25006718 - letrozole vs clomiphene in PCOS
• 8 - PMID 28610678 - Anti-Müllerian hormone, follicle stimulating hormone, antral follicle count, and risk of menopause within 5 years, Maturitas (2017)
• 9 - PMID 31329213 - Diagnosing the Onset of Menopause, JAMA (2019)
• 10 - PMID 34228062 - Diagnosis and Management of Infertility, JAMA (2021)
• 11 - International Evidence-based Guideline for the assessment and management of polycystic ovary syndrome 2023
• 12 - PMID 27406348 - CLINICAL PRACTICE. Polycystic Ovary Syndrome, NEJM (2016)
• 13 - PMID 30604525 - The efficacy and use of finasteride in women: a systematic review, Int J Dermatol (2019)