- ACRONYMS AND DEFINITIONS
- FSH - Follicle stimulating hormone
- HPO - Hypothalamic-pituitary-ovarian
- ICSI - Intracytoplasmic sperm injection
- IUI - Intrauterine insemination
- IVF - In vitro fertilization
- LH - Luteinizing hormone
- PCOS - Polycystic ovarian syndrome
- RCT - Randomized controlled trial
- SERM - Selective estrogen receptor modulator
Follicle-stimulating hormone (FSH)
Luteinizing hormone (LH)
- HYPOTHALAMIC-PITUITARY-OVARIAN AXIS
- MENSTRUAL CYCLE
- Menses (days 0 - 5) - menses occurs at the end of the previous luteal phase. When the corpus luteum regresses, it stops secreting progesterone and estrogen. The endometrium undergoes necrosis and sloughs off. Menses occurs during days 0 - 5 of the typical 28-day menstrual cycle.
- Follicular phase (days 1 - 13) - the follicular phase of the menstrual cycle is the phase in which a mature follicle develops inside the ovary. The follicular phase occurs during the first 13 days of a typical 28-day menstrual cycle. The follicle is stimulated by Follicle Stimulating Hormone (FSH) that is released by the pituitary. A developing follicle secretes estradiol up to the point that ovulation occurs, at which time it enters the luteal phase.
- Ovulation (days 13 - 14) - ovulation occurs when an egg from a mature follicle is released from the ovary. Ovulation typically occurs on days 13 - 14 of a typical 28-day menstrual cycle.
- Luteal phase (days 14 - 28) - the luteal phase of the menstrual cycle is the phase in which the evacuated follicle turns into the corpus luteum. The corpus luteum secretes progesterone which causes the endometrium to become secretory, preparing it for ovum implantation. The corpus luteum is stimulated by Luteinizing Hormone (LH) that is released by the pituitary. The luteal phase occurs during days 14 - 28 of a typical 28-day menstrual cycle. The corpus luteum secretes progesterone and estrogen up until days 24 - 26, at which point, hormone levels plunge, and the endometrium is no longer supported. Menses then occurs.
- Menopause occurs when ovarian follicles are depleted and the production of estrogen and progesterone ceases
- Twelve consecutive months without menses is the general 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. 
- 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 begin 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. 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. 
- 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 and then followed them longitudinally for the onset of menopause are presented in the tables below
|% of women achieving menopause within 5 years based on 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%|
|% of women achieving menopause within 5 years based on 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%|
Gonadotropins (Gonal-f®, Menopur®)
- 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
- 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.
- 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
- 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
- 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
- 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.
- 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.
- 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.
- 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
- 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
- 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
- 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.
- 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
- 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.
- 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
- 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.
- 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
- 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.
- 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
- 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.
- 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
- 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.
- 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
- 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
- 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
- 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.
- 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.
- 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.
|SERM ACTIVITY TABLE|
|No data||Neutral to
- 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)