Integrative Approaches to Infertility: Women

Integrative Approaches to
Infertility: Women
DR. JACLYN CHASSE, ND
Infertility on the Rise
“Infertility”, or difficulty conceiving, affects about
11.8% of the population 1
Published rates of infertility vary from 5% to 17% in
the US, depending on the source
1. Fertility, Family Planning, and Reproductive Health of U.S. Women: Data from the 2002 National Survey of Family Growth, tables 67, 69, 97
Trends in the percentage
of women (aged 15-44
years) with impaired
fecundity by age group,
1982-2002
CDC Report: “Fertility, Family
Planning and Reproductive
Health of US Women: Data from
the 2002 National Survey of
Family Growth” National Center
for Health Statistics, Vital Health
Stat 23(25) (2005).
1982
1988
1995
Fertility in the US
Where are we and why?
2002
2012
What is Infertility?
Different definitions
Generally, 1 year of well-timed unprotected
intercourse not resulting in pregnancy OR
Multiple miscarraiges
Most couples seek help sooner than 1 year into the
process.
What is Infertility?
Infertility: The inability to conceive and produce a live-born
offspring 1
Subfertility: Difficulty conceiving and producing live-born
offspring
Fecundibility: The probability of conceiving during any one
menstrual cycle
Fecundity: The ability to achieve a pregnancy that results in a live
birth in 1 cycle
Sterility: Irreversible infertility
1. Yen SSC, et al. Reproductive Endocrinology: Physiology, Pathophysiology and Clinical Management. 4th edition. Philadelphia, PA. Saunders
Company 1999.
What is Infertility?
Clinical definition of Infertility: Inability to
conceive after 12 months of unprotected, frequent
intercourse
“The inability to conceive when you want”2
Growing issue with conception at an advanced age
2. Hays, Bethany. Infertility: A Functional Medicine Approach. Integrative Medicine 2009; 8(6):20-27.
Typical Fertility
80-90% of couples attempting to conceive will fall
pregnant within 1 year and 95% within 2 years.
Chances of becoming pregnant decrease with age and
with the length of infertility
Typical Fertility
40% of the time it is due to a female factor
40% of the time it is due to a male factor
The other 20% include a combination of factors and
unexplained infertility.
Explained vs Unexplained Infertility
When a couple presents with difficulty conceiving,
both partners go through a workup
Tests abnormal? Explained infertility
Ie Low sperm count
Ie. Tubal occlusion
Tests normal? Unexplained infertility
Growing number of cases!
A rapid-fire review
Quick Review
The Menstrual Cycle
Female Causes of Infertility
OVERVIEW
FINDING THE CAUSE: THE CONSULT
Causes of Fertility Challenges
Ovulatory: Ovarian defects, anovulatory cycles, hyperprolactinemia, hypothalamic
dysfunction, pituitary dysfunction, premature ovarian failure, ovarian resistance
Metabolic: thyroid, adrenal disorders, liver or renal disease, androgen excess
(adrenal or neoplastic causes)
Pelvic: STI, chronic inflammation including PID, fallopian tube adhesions, fibroids,
endometriosis, structural abnormalities
Cervical: hostile mucous, cervicitis, acquired cervical damage to mucous-producing
glands due to cone biopsy, colposcopy, or cryotherapy
Immune-mediated: lack of blocking antibodies, AI disease, immuniphenotypes,
anti-thyroid antibodies, antiphospholipid syndrome
Most common medical causes of Infertility
Scar Tissue
PID
Fibroids
PCOS/Ovarian Cysts
Endometriosis
Thyroid Disease
The consult: complete history
Chief complaint: Infertility
Duration of infertility
Previous eval/treatment & results
Medical history including menstrual history
Age at menarche, cycle length, characteristics
Past surgeries, pelvic injury/infection, abnml paps & tx
Thyroid, galactorrhea, hirsutism, pelvic/abd pain
Sexual history
Pg history (gravidity, parity, pg outcome, associated complications)
Previous contraception
Coital frequency and sexual dysfunction/dyspareunia
Family history
Early menopause, reproductive challenges, birth defects, mental retardation
Meds and supplements
Social habits
Occupational history
The consult: PE
Weight/BMI and other vitals
Thyroid enlargement or abnormalaties
Breast secretions
Signs of androgen excess (ie hirsutism, acne, etc)
Vaginal/cervical abnormality
Uterine size/shape, position, mobility
Lab workup
Step 1 labs
CBC
Blood Type
TSH with reflex antibodies
CMP
Fasting blood glucose
Ferritin
Vitamin D
Vitamin B12, Homocysteine
Prenatal panel: Hep B/C, GC/CT, CMV, Varicella, Parvovirus,
Herpes, Toxoplasmosis, HIV, Syphilis
Hormones:
Day 3: Estrogen, LH, FSH, Prolactin, Testosterone, FAI, SHBG
Day 21: Progesterone
Hormones
Estrogen
Day 3 >50 ng/mL can be an indicator of poor egg quality
Progesterone
Serum level >3/6/10 ng/mL indicates ovulation has taken place
Mid luteal progesterone >10 ng/mL is associated with a better percycle pregnancy rate
Hormone Labs
39 yo female with multiple miscarraiges
Other lab/imaging considerations
Screen for autoimmune disorders
Cervical cytology (pap)
Heavy metal screening
Adrenal testing (salivary)
Hysterosalpingogram (HSG)
Transvaginal ultrasound (to evaluate developing follicles on
ovary, screen for cysts, etc)
Laparoscopy (tubal abnormalaties, endometriosis)
Serum testing for immune mediated infertilily (will be discussed
with miscarraiges)
Post-coital testing
Progesterone withdrawal challenge
Improving Female Factor
Infertility
POOR EGG QUALITY
PCOS
THIN UTERINE LINING
IRREGULAR CYCLES
RECURRENT MISCARRAIGE
Ovarian failure and Poor Egg Quality
FSH <10 mIU/mL best.
FSH > 25 mIU/mL had ongoing pregnancy rate of
0% in one study
Sometimes, antral follicle count is used as well
(want more than 6 follicles present)
Generally, recommended that they consider egg
donation
Other markers for ovarian reserve
Antral Follicle Count: Number of follicles
detected by U/S (>2mm)
Anti-mullerian hormone (AMH)
Made by preantral follicles (follicles in development)
Lower AMH usually correlates with lower AFC
Doesn’t change much through menstrual cycle
Antral Follicle Counts
AMH Levels
Ovarian Fertility Potential
Pmol/L
Ng/mL
Optimal fertility
28.6-48.5
4.0-6.8
Satisfactory fertility
15.7-28.6
2.2-4.0
Low fertility
2.2-15.7
0.3-2.2
Very low/undetectable
0.0-2.2
0.0-0..3
Egg Quality
As you would predict, oxidative stress also plays a
significant role in egg quality.
Poor Egg Quality
Melatonin and IVF
Italian study, 65 women undergoing IVF randomized to
receive myo-inositol and folate or the same combination plus
melatonin.
Significant increased number of mature oocytes and decreased
number of immature oocytes (no difference in total number)
after GnRH stimulation in the melatonin group
Positive trends in clinical pregnancy rate and implantation rate
(non-significant)
Many studies have mirrored these results
Rizzo P et al. Eur Rev Med Pharmacol Sci. 2010;14(6):555-61.
Batioqlu AS et al. Gynecol Endocrinol. 2012;28(2):91-3
Poor Egg Quality
Melatonin (cont.)
115 women with history of failed IVF and low fertilization rate
(<50%) in previous IVF cycle
Melatonin 3mg/day or
No intervention
Fertilization rate significantly improved in melatonin group
only
Tamura H. et al. J Pineal Res. 2008;44(3):280-7.
Unfer V et al. Gynecol Endocrinol. 2011;27(11):857-61.
Poor Egg Quality
DHEA
Used by 1/3 of all IVF centers worldwide
Improves ovarian function and ovarian reserve
Promote preantral follicle growth and reduction in follicle atresia
Increases pregnancy rates with IVF
Lowers miscarriage rates by reducing aneuploidy, especially in
women over age 35
Gleicher N. Reprod Biol Endocrinol. 2011;9:67.
Gleicher N et al. Reprod Biol Endocrinol. 2009;7:108.
Poor Egg Quality
DHEA
Supplementation with 25 mg three times daily significantly
improved AMH (Anti-mulerian hormone) (p=0.002),
especially for women under age 38.
Improvement of AMH was about 60% (p<0.0002)
Longer use showed greater improvement up to 120 days.
Significant increases in fertilized oocytes (P<0.001), normal
day 3 embryos (P=0.001), transferred embryos (P=0.005), and
improved embryo scores (P<0.001).
Gleicher N. Reprod biomed Online. 2010;21(3):360-5.
Barad D et al. Hum Reprod. 2006;21(11):2845-9.
Poor Egg Quality/ Premature Ovarian Failure
Sample treatment plan
General mind/body support
Example formula:
Tribulus 80mL (tablet is often better due to high
concentrations needed) – botanical alternative to DHEA
Shatavari 10mL
Vitex 5mL
Dioscorea 5mL
Dose 20mL bid
DHEA 25mg tid
Melatonin 3 mg hs
CoQ10, arginine, acetyl-L-carnitine, other favorite antioxidants
Poor Egg Quality
Case Study
Carrie P.
Sample protocol
Prenatal
Fish oil 2 grams
DHEA 25 mg tid
Melatonin 3 mg hs
Antioxidant formula
Vitamins A, C, E
Zinc, selenium
CoQ10
Glutathione
Green tea, resveratrol,
curcumin
Patients, beware!
Caution your IVF patients after going through these
protocols for egg quality!
Case study: Laurie B.
PCOS:
The most common hormonal cause of infertility
Symptoms
Hirsutism
Oligo or amenorrhea
Obesity
Infertility
Signs
Bilateral polycystic ovaries
Elevated LH and LH to FSH ratio
Oligoovulation
Elevated free testosterone and DHEAS
Glucose intolerance and elevated insulin
PCOS
In PCOS, GnRH pulsatile frequency is higher than normal
increased circulating LH and decreased FSH
Leads to excessive production of androstenedione and
testosterone
FSH triggers follicular growth, but not to maturity atresia
of follicle into cyst
Estrogen increased due to peripheral conversion of increased
androstenedione estrogen
Lack of progesterone allows continued pulsitile secretion of
GnRH
PCOS
Likely also genetic mutation of CYP17 enzyme,
responsible for forming androgens from DHEA-S
High androgens inhibit FSH
Often also hyperprolactinemia
PCOS Tx goals
Improve stress response/HPA function
(adaptogens like eleuthero, licorice, ginseng,
rhodiola, schisandra, ashwagandha,)
Hormone regulation (increased progesterone
secretion, LH:FSH, decrease prolactin): Licorice,
white peony, tribulus, vitex
Blood sugar regulation (Gymnema)
PCOS
Affects 10% of women of reproductive age
Anovulation or irregular menses
Elevated LH/FSH, elevated testosterone, elevated prolactin
Current standard of care is insulin sensitizing agents
such as metformin, but metformin doesn’t enhance
ovulation in many patients.
Studies have demonstrated superior effect of inositol
in:
Sensitizing cells to insulin in PCOS patients
Restoring ovulation
Nestler JE. NEJM. 1998;338(26):1876-80.
Sturrock ND. Br J Clin Pharmacol. 2002;53(5):469-73.
Inositol and PCOS
Phosphoglycan that mediates insulin action contains
d-chiro-inositol
This phosphoglycan is deficient in PCOS patients
Administration of inositol
Improves insulin sensitivity
Improves ovulatory function
Decreases serum androgens
Decreases elevated blood pressure
Decreases elevated plasma triglycerides
Improves oocyte quality in women with PCOS
Galletta M. et al. Eur Rev Med Pharmacol Sci. 2011;15(10):1212-4.
Nestler JE et al. NEJM. 1999;340(17):1314-20.
Ciotta L. Eur Rev Med Pharmacol Sci. 2011;15(5):509-14.
PCOS
Myo-inositol seems to perform better then d-chiro
inositol
Standard dosage 4g/day
Galletta M. et al. Eur Rev Med Pharmacol Sci. 2011;15(10):1212-4.
PCOS
Other useful therapeutics: vitex, licorice/peony
combination (shakuyaki-kanzo-to)
In women undergoing clomid-supported cycles,
coadministration of N-acetyl-cysteine 1200mg/day
cd 3-8 showed improvement in ovulation rate (52.1%
vs. 17.9%), mature follicles, endometrial thickness,
follicular E2 levels, and luteal P levels.
Badawy A et al. Acta Obstet Gynecol Scand. 2007;86(2):218-22.
PCOS and Infertility
Sample treatment plan
Preconception support
Exercise and Diet!
Green tea consumption
Example formula:
Licorice
White Peony
Vitex
Gymnema
Saw palmetto
Schisandra/ashwagandha/holy basil
Chromium 200 mcg
N-Acetyl Cysteine 1200 mg/day
Myo-Inositol 4g/day
Thin Uterine Lining
Common side effect of clomid, letrozole, and other
ovulation induction meds is a thinner endometrial
lining
This can prevent proper implantation
No research to support, but Shatavari can be helpful
to mitigate this effect.
Cycle Abnormalaties: Luteal Phase Defect
Defined by shortened luteal phase or inadequate
production of progesterone
Timing is vital for proper implantation!
Egg/embryo takes 7 days to get from ovary to implantation in
the uterus
Cytokine/prostaglandin cascade triggering menstruation
begins 3-4 days before menstruation onset
Need long enough luteal phase to allow for implantation and
continuation of progesterone synthesis by corpus luteum.
Cycle Abnormality:
Luteal Phase Insufficiency
“Going out of favor” in conventional fertility
circles
Used to think it involved delayed maturation of
endometrium
Also likely related to insufficiency of progesterone
or inefficient priming of corpus luteum
Luteal Phase Deficiency
Treatment includes support of estrogen to support
proper LH surge
Progesterone support after ovulation to lengthen
cycle
Example formula: Peonia 50mL, Vitex 15mL,
Glycyrrhiza 25mL, Caulophyllum 10mL
Dose 5mL tid throughout cycle
Add biphasic tinctures
Vitex
Vitex may help lengthen the luteal phase, decrease prolactin,
and restore ovulation.
Study on 30 infertile women
Given proprietary supplement with vitex, green tea extract, Larginine, vitamins (including folate) and minerals
After 3m, supplement group had increased midluteal progesterone
and increased BBT in luteal phase
After 5 mo, 1/3 women in treatment group were pregnant and none
of the 15 women in placebo group were pregnant
Cycle Abnormalaties: Luteal Phase Defect
Animal models have suggested that oxidative stress
can impair ovarian development of corpus luteum,
leading to low progesterone.
In humans, melatonin treatment (3 mg/day at
10pm) through the luteal phase increased serum
progesterone concentrations compared to
unmedicated group.
Noda Y. et al. Biol Reprod. 2012;86(1):1-8.
Taketani T. J Pineal Res. 2011;51(2):207-13.
Case: Melissa and Dan
Mercer and Miranda
Causes of Fertility Challenges
Ovulatory: Ovarian defects, anovulatory cycles, hyperprolactinemia, hypothalamic
dysfunction, pituitary dysfunction, premature ovarian failure, ovarian resistance (15% of all
infertile couples, 40% of infertility in women)
Metabolic: thyroid, adrenal disorders, liver or renal disease, androgen excess
(adrenal or neoplastic causes)
Pelvic: STI, chronic inflammation including PID, fallopian tube adhesions, fibroids,
endometriosis, structural abnormalities
Cervical: hostile mucous, cervicitis, acquired cervical damage to mucous-producing
glands due to cone biopsy, colposcopy, or cryotherapy
Immune-mediated: lack of blocking antibodies, AI disease, immuniphenotypes,
anti-thyroid antibodies, antiphospholipid syndrome
Mosher WD, Pratt WF. Fecundity and infertility in the United States: incidence and trends. Fertil Steril 1991;56:192
Pregnancy Loss
Managing Miscarriage
Many patients want workup sooner than medical
standard
After 1 miscarriage, likelihood of next pregnancy healthy is
76%
After 2, 70%
After 3, 65%
After 4, 60%
Work-up after 2 consecutive losses if no prior term
pregnancies, after 3 if prior term-pregnancy
Miscarriage
Fetal Stage
Timing
Key milestones
Contributing factors
Preembryonic
LMP to
week 4
Implantation
Genetic, implantation-related
(thrombotic, thin uterine
lining, low P)
Embryonic
Week 5-9
Organogenesis
O2 and nutrients
through placenta
Genetic, hormonal (low P)
Fetal
Week 10delivery
Autoimmune, thrombotic,
anatomic
Miscarriage
No research supporting specific clinical interventions
for pregnancy loss, but consider your naturopathic
therapeutics
Suspected
Cause
Considerations
Genetic
Oxidative stress, toxic burden, etc
Thrombotic
Aspirin, blood-thinning herbs, omega 3s, etc
Immune
Evaluate possibility of food intolerance, manage with favorite
auto-immune protocol
Unexplained Infertility
TAKING A NATUROPATHIC LOOK
INTEGRATIVE TREATMENT OPTIONS
Unexplained Infertility
Consider other compounding factors
Food intolerance/celiac disease
Chronic inflammation
Toxicity (heavy metal or otherwise)
Exposure to endocrine-disrupting compounds
Stress
Low nutrient status
Emotional/spiritual state
Institute the classic naturopathic tools!
Heavy Metals and Fertility/IVF
UK study of 30 women with failed IVF history
Hair mineral/metal analysis completed.
Hair mercury concentration negatively correlated
with oocyte yield (p<0.05) and follicle number
(p<0.03)
Hair zinc and selenium positively correlated with
oocyte yield (p<0.05) and follicle number (p=0.03).
Dickerson EH et al. J Assist Reprod Genet. 2011;28(12):1223-8.
It’s not just about getting
pregnant…
KNOWN AND SUSPECTED RISKS OF ADVANCED
FERTILITY TREATMENT
LOWERING THE RISK
Are there risks of fertility technologies?
Most risk associated with greatest level of
intervention
IVF with ICSI
Bypassing mother nature’s limitations around who can conceive
Manual selection of sperm based on gross morphology
Either egg or sperm (or both) may not have been good enough
quality to conceive on own
Are there risks of fertility technologies?
Obesity
Female teens born through ICSI have significantly higher rates
of obesity (compared to spontaneous conception group).
Measured higher peripheral adiposity (skin fold measurement,
upper arm circumference) and central adiposity (skin fold
measurement, waist circumference), and total adiposity (BMI)
(p<0.05)
Neither parental or early life factors could explain the differences
Same trend not observed in males
Belva F et al. Hum Reprod. 2012 Jan;27(1):257-64.
Risk of ART
ART, especially ICSI, alters natural selection.
Increased rates of chromosomal abnormalaties
Increased rates of hypospadias, Angelman syndrome, Beckwith-Wiedemann
syndrome
Developmental delays and defects (subtle) have been reported. Increased rates
of ADHD, Autism. Could there be more?
The Bottom Line
IM is KEY for Fertility!
Integrative medicine provides effective fertility
support for most couples and incorporates all
principles of naturopathic medicine
Thank you!
Jaclyn Chasse
[email protected]
www.northeastintegrative.com
Recommended Resources
Reproductive Endocrinology: Physiology,
Pathophysiology, and Clinical Management. Yen
SSC, Jaffee RB, and Barbieri RL. 4th Ed.
Philadelphia, PA: W.B. Saunders Company; 1999.
Having Faith. Sandra Steingraber
Botanical Medicine for Women’s Health. Aviva
Romm
Women, Hormones, and the Menstrual Cycle.
Charting your Cycle
Textbook of Functional Medicine. Jones DS, Quinn S.
Resources
Greco, E. ICSI in cases of sperm DNA damage: beneficial effect of oral antioxidany treatment. Centre for Repro. Mgmt.
Rome, Italy.
Silver, EW et. al. Effect of antioxidant intake on sperm chromatin stability in healthy nonsmoking men. J Androl. 2005
Jul-Aug;26(4): 550-6.
Balceria G, et. al. Placeb-controlled double-blind randomized trial on the use of L-carnitine, L-acetylcarnitine, or
combined L-carnitine and L-acetylcarnitine in men with idiopathic athenozoospermia. Fertil Steril. 2005
Sep;84(3):662-71.
Wong WY et.al. Effects of folic acid and zinc sulfate on male factor infertility: a double-blind, randomized, placebocontrolled trial. Fertil Steril. 2002 Mar;77(3):491-8.
Casini ML et al. An infertile couple suffering from oligospermia by partial sperm maturation arrest: can phytoestrogens
play a therapeutic role? A case study report. Gynecol Endocrinol. 2006 Jul;22(7):399-401.
Resources
Agarwal et. al. Reactive oxygen species as an independant marker of male factor infertility. Fertil Steril. 2006 Oct; 86(4): 878-85.
Sami et. al. Health seeking behavior of couples with secondary infertility. J Coll Physicians Surg Pak. 2006 Apr. 16(4):261-4.
Chan CH. Body-mind-spirit intervention for IVF women. J Assist Reprod Genet. 2005 Dec;22(11-12):419-27
Roemheld-Hamm B. Chasteberry. Am Fam Physician. 2005 Sep 1;72(5):821-4
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contolled, randomized trial. Fertil Steril. 2004 Dec;82(6):1509-13
Cwikel J et. al. Psychological interactions with infertility among women. Eur J Obstet Gynecol Reprod Biol. 2004 Dec 1;117(2):12631
Unfer V et. al. High dose of phytoestrogens can reverse the antiestrogenic effects of clomiphene citrate on the endometrium in
patients undergoing intrauterine insemination: a randomized trial. J Soc Gynecol Investig. 2004 Jul;11(5):323-8
Westphal et. al. A nutritional supplement for improving fertility in women: a pilot study. J Repro Med. 2004 Apr;49(4):289-93
Ventegodt et. al. Clinical holistic medicine: holistic pelvic examination and holistic treatment of infertility. Scientific World Journal.
2004 Mar 4;4:148-58
Resources
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de Weerd et. al. Preconception counseling improves folate status of women planning pregnancy. Obstet Gynecol. 2002
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Foresight Association: www.foresight-preconception.org.uk