Protocol development in integrative medicine is not typically a simple process. Individuals require individualized care, and what works for one patient may not work for another.
To establish these protocols, we first developed a Rating Scale that could be used to discern the rigor of evidence supporting a specific nutrient’s therapeutic effect.
The following protocols were developed using only A through C-quality evidence.
Infertility affects approximately 10 to 15% of couples. (12) While the causes of infertility vary and can be linked both to male and female conditions, one contributing factor may be hormonal dysfunction in women. (2)
Testing levels of hormones, such as estrogen, progesterone, testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone, can all assist in identifying imbalances and addressing hormonal dysfunction in women. Hormone dysfunction may contribute to changes in ovulation rates or anovulation, and correcting levels of hormones may improve pregnancy success and reduce the probability of miscarriage. (7)(20)(23)
A number of factors may contribute to hormonal dysfunction, including environmental disturbances. Research suggests that endocrine disruptors, which may be present in air pollution, are correlated with increased rates of miscarriage, reduced live birth rates, and increased levels of nitrogen dioxide and ozone in populations undergoing in vitro fertilization (IVF). (5)
In addition, hormonal dysfunction is commonly seen in conditions such as polycystic ovarian syndrome (PCOS). Low serum vitamin D in women with PCOS appears to be correlated with endocrine disturbances. (1) Addressing imbalances in hormones, such as androgens, testosterone, and dehydroepiandrosterone, may be beneficial in the treatment of PCOS. (5) Improving the quality and maturation of oocytes also demonstrates promising results in women with or without PCOS undergoing ovulation induction. (3)(20)
Based on current research findings, the ingredients in the protocol below have demonstrated efficacy in improving a variety of factors associated with female fertility.
- Poor responders undergoing intracytoplasmic sperm injection (ICSI) who received myo-inositol and folic acid supplementation experienced improved ovarian responses to gonadotropins, demonstrated by higher ovarian sensitivity index scores, as well as increased mature metaphase II oocytes rates and reduced total rec-FSH units compared to patients who received folic acid alone (3)
- Supplementation of myo-inositol three months prior to follicular stimulation and in vitro insemination reduced the number of mature oocytes, improved total gonadotropin scores correlating with an increase in implantation rate, and subsequently reduced the total required dose of rFSH (13)
- Meta-analysis of 10 randomized trials found myo-inositol or D-chiro-inositol supplementation increased the frequency of menstrual cycles and improved ovulation rate with or without metformin administration (20)
- Myo-inositol improves sensitivity to clomiphene citrate, demonstrated by increased ovulation rates from 42% to 65.5% and pregnancy rates from 42.4% to 53.8% when compared to a historical cohort (21)
- Infertile PCOS patients undergoing intrauterine insemination (IUI) who received myo-inositol prior to controlled ovulation induction (COH) experienced less canceled cycles and increased rates of pregnancy and number of spontaneous pregnancies, resulting in lower rFSH dose requirements and duration of ovulation induction (11)
- Repletion of vitamin D increases clinical pregnancy rates, the likelihood of positive pregnancy tests, and live birth rates in vitamin D-deficient individuals undergoing assisted reproductive technology (ART) when compared to a control group (4)
- Vitamin D regulated Anti-Müllerian hormone (AMH) as shown by an increase in AMH after supplementation in women aged 18 to 25 years old when supplemented (9)
- Premenopausal women were found to experience an 18% decrease of AMH levels in winter compared to summer; supplementation was found to prevent seasonal decrease (8)
- Systematic review and meta-analysis of 24 studies found Anti-Müllerian hormone (AMH) levels to decrease after vitamin D supplementation in patients with PCOS, and increase in supplementation in women without PCOS (15)
Prenatal formulation including 800 mcg folic acid, 28 days prior to conception and continued through the second missed menstrual period, or prenatal formulation including 800 mcg folic acid, 4-6 weeks prior to ovulation induction (1)(6)
- Systematic review of five studies found supplementation of multivitamin for 28 days prior to conception and through the second missed menstrual period positively increased fertility from 2.7% to 3.8%, measured by cumulative conceptions and multiple births, and reduced neural tube defects in women with or without ovarian stimulation (6)
- Subfertile women treated with clomiphene citrate and gonadotropins undergoing ovulation induction experienced higher pregnancy rates (66.7%) and required fewer pregnancy attempts with concomitant multiple micronutrient supplementation compared to folic acid alone (39.3%) (1)
- Micronutrient supplementation improved pregnancy rates and live birth rates when administered during in-vitro fertilization (IVF) therapy (2)
- NAC administered concomitantly in clomiphene citrate-resistant patients with PCOS was associated with increased ovulation and pregnancy rates (19)
- When comparing clomiphene citrate treatment alone to concomitant treatment with NAC or metformin in PCOS patients, the group receiving NAC experienced higher rates of pregnancy (20% compared to 10% in the clomiphene citrate and clomiphene citrate/metformin groups), improved ovulation and peak endometrial thickness (14)
- Ovulation and pregnancy rates improved as well as ideal endometrial thickness in infertile women with PCOS (22)
- NAC administered with unilateral laparoscopic ovarian drilling (LOD) in clomiphene citrate-resistant PCOS patients was associated with increased ovulation rates from 67% to 87% and pregnancy rates from 57% to 77%, lowered miscarriage rates from 23.5% to 8.7%, and subsequent live birth rates of 67% compared to 40% in the placebo group (17)
Ashwagandha (Withania somnifera)
300 mg (e.g. KSM-66 extract), twice per day, for 8 weeks (10)
- Ashwagandha supplementation was associated with enhanced sexual behavior in females as measured by the female sexual function index (FSFI) and female sexual distress index (FSDI) (19)
- Supplementation improved FSFI and FSDS scores, and increased number of sexual encounters (10)
- Ashwagandha supplementation improved sexual function, demonstrated by an increase in FSFI score by 122.67%, accounting for improvements in arousal (62.09%), lubrication (59.30%), orgasm (82.05%), and satisfaction (62.33%) when compared to baseline (10)
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- Agrawal, R., Burt, E., Gallagher, A. M., Butler, L., Venkatakrishnan, R., & Peitsidis, P. (2012). Prospective randomized trial of multiple micronutrients in subfertile women undergoing ovulation induction: a pilot study. Reproductive Biomedicine Online, 24(1), 54–60. https://pubmed.ncbi.nlm.nih.gov/22138521/ (C)
- Arhin, S. K., Zhao, Y., Lu, X., Chetry, M., & Lu, J. (2017). Effect of micronutrient supplementation on IVF outcomes: a systematic review of the literature. Reproductive Biomedicine Online, 35(6), 715–722. https://pubmed.ncbi.nlm.nih.gov/28919239/ (A)
- Caprio, F., D’Eufemia, M. D., Trotta, C., Campitiello, M. R., Ianniello, R., Mele, D., & Colacurci, N. (2015b). Myo-inositol therapy for poor-responders during IVF: a prospective controlled observational trial. Journal of Ovarian Research, 8, 37. https://pubmed.ncbi.nlm.nih.gov/26067283/ (C)
- Chu, J., Gallos, I., Tobias, A., Tan, B., Eapen, A., & Coomarasamy, A. (2018). Vitamin D and assisted reproductive treatment outcome: a systematic review and meta-analysis. Human Reproduction , 33(1), 65–80. https://pubmed.ncbi.nlm.nih.gov/29149263/ (A)
- Conforti, A., Mascia, M., Cioffi, G., De Angelis, C., Coppola, G., De Rosa, P., Pivonello, R., Alviggi, C., & De Placido, G. (2018). Air pollution and female fertility: a systematic review of literature. Reproductive Biology and Endocrinology: RB&E, 16(1), 117. https://pubmed.ncbi.nlm.nih.gov/30594197/ (A)
- Czeizel, A. E., Dudás, I., & Métneki, J. (1994). Pregnancy outcomes in a randomised controlled trial of periconceptional multivitamin supplementation. Final report. Archives of Gynecology and Obstetrics, 255(3), 131–139. https://pubmed.ncbi.nlm.nih.gov/7979565/ (C)
- Czeizel, A. E., Métneki, J., & Dudás, I. (1994). The higher rate of multiple births after periconceptional multivitamin supplementation: an analysis of causes. Acta Geneticae Medicae et Gemellologiae, 43(3-4), 175–184. https://pubmed.ncbi.nlm.nih.gov/8588492/ (C)
- Dennis, N. A., Houghton, L. A., Jones, G. T., van Rij, A. M., Morgan, K., & McLennan, I. S. (2012). The level of serum anti-Müllerian hormone correlates with vitamin D status in men and women but not in boys. The Journal of Clinical Endocrinology and Metabolism, 97(7), 2450–2455. https://pubmed.ncbi.nlm.nih.gov/22508713/ (C)
- Dennis, N. A., Houghton, L. A., Pankhurst, M. W., Harper, M. J., & McLennan, I. S. (2017). Acute Supplementation with High Dose Vitamin D3 Increases Serum Anti-Müllerian Hormone in Young Women. Nutrients, 9(7). https://pubmed.ncbi.nlm.nih.gov/28698476/ (C)
- Dongre, S., Langade, D., & Bhattacharyya, S. (2015). Efficacy and Safety of Ashwagandha (Withania somnifera) Root Extract in Improving Sexual Function in Women: A Pilot Study. BioMed Research International, 2015, 284154. https://pubmed.ncbi.nlm.nih.gov/26504795/ (C)
- Emekçi Özay, Ö., Özay, A. C., Çağlıyan, E., Okyay, R. E., & Gülekli, B. (2017). Myo-inositol administration positively effects ovulation induction and intrauterine insemination in patients with polycystic ovary syndrome: a prospective, controlled, randomized trial. Gynecological Endocrinology: The Official Journal of the International Society of Gynecological Endocrinology, 33(7), 524–528. https://pubmed.ncbi.nlm.nih.gov/28277112/ (C)
- Lerchbaum, E., & Obermayer-Pietsch, B. (2012). Vitamin D and fertility: a systematic review. European Journal of Endocrinology / European Federation of Endocrine Societies, 166(5), 765–778. https://pubmed.ncbi.nlm.nih.gov/22275473/ (A)
- Lisi, F., Carfagna, P., Oliva, M. M., Rago, R., Lisi, R., Poverini, R., Manna, C., Vaquero, E., Caserta, D., Raparelli, V., Marci, R., & Moscarini, M. (2012). Pretreatment with myo-inositol in non polycystic ovary syndrome patients undergoing multiple follicular stimulation for IVF: a pilot study. Reproductive Biology and Endocrinology: RB&E, 10, 52. https://pubmed.ncbi.nlm.nih.gov/22823904/ (C)
- Maged, A. M., Elsawah, H., Abdelhafez, A., Bakry, A., & Mostafa, W. A. (2015). The adjuvant effect of metformin and N-acetylcysteine to clomiphene citrate in induction of ovulation in patients with Polycystic Ovary Syndrome. Gynecological Endocrinology: The Official Journal of the International Society of Gynecological Endocrinology, 31(8), 635–638. https://pubmed.ncbi.nlm.nih.gov/26291797/ (C)
- Moridi, I., Chen, A., Tal, O., & Tal, R. (2020). The Association between Vitamin D and Anti-Müllerian Hormone: A Systematic Review and Meta-Analysis. Nutrients, 12(6). https://pubmed.ncbi.nlm.nih.gov/32481491/ (A)
- Nasr, A. (2010). Effect of N-acetyl-cysteine after ovarian drilling in clomiphene citrate-resistant PCOS women: a pilot study. Reproductive Biomedicine Online, 20(3), 403–409. https://pubmed.ncbi.nlm.nih.gov/20089454/ (B)
- Pundir, J., Psaroudakis, D., Savnur, P., Bhide, P., Sabatini, L., Teede, H., Coomarasamy, A., & Thangaratinam, S. (2018). Inositol treatment of anovulation in women with polycystic ovary syndrome: a meta-analysis of randomised trials. BJOG: An International Journal of Obstetrics and Gynaecology, 125(3), 299–308. https://pubmed.ncbi.nlm.nih.gov/28544572/ (A)
- Rolland, A.-L., Peigné, M., Plouvier, P., Dumont, A., Catteau-Jonard, S., & Dewailly, D. (2017). Could myo-inositol soft gel capsules outperform clomiphene in inducing ovulation? Results of a pilot study. European Review for Medical and Pharmacological Sciences, 21(2 Suppl), 10–14. https://pubmed.ncbi.nlm.nih.gov/28724178/ (C)
- Salehpour, S., Sene, A. A., Saharkhiz, N., Sohrabi, M. R., & Moghimian, F. (2012). N-Acetylcysteine as an adjuvant to clomiphene citrate for successful induction of ovulation in infertile patients with polycystic ovary syndrome. The Journal of Obstetrics and Gynaecology Research, 38(9), 1182–1186. https://pubmed.ncbi.nlm.nih.gov/22540635/ (B)
- Shang, W., Wang, A., Lv, L., Zhang, L., Shu, M., Zhao, Y., & Hui, S. (2015). Individualized Hormone Adjustment in the Treatment of Recurrent Spontaneous Abortions. Cell Biochemistry and Biophysics, 72(3), 817–820. https://pubmed.ncbi.nlm.nih.gov/25638341/ (C)
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