Please select the eligibility criteria that correspond to the clinical trial below.
Title: Males, Antioxidants, and Infertility (MOXI) Trial
Brief Summary: The objective of the Males, Antioxidants, and Infertility (MOXI) Trial is to examine whether treatment of infertile males with an antioxidant formulation improves male fertility. The central hypothesis is that treatment of infertile males with antioxidants will improve sperm structure and function, resulting in higher fertilization rates and improved embryo development, leading to higher pregnancy and live birth rates. Findings from this research will be significant in that they will likely lead to an effective, non-hormonal treatment modality for male infertility. An effective treatment for men would also reduce the treatment burden on the female partner, lower costs, and provide effective alternatives to couples with religious or ethical contraindications to ART (Assisted Reproductive Technology). If antioxidants do not improve pregnancy rates, but do improve sperm motility and DNA integrity, they could allow for couples with male factor infertility to use less intensive therapies such as intrauterine insemination. Male fertility specialists currently prescribe antioxidants based on the limited data supporting their use. A negative finding, lack of any benefit, would also alter current treatment of infertile males.


Options:
A: Couples Inclusion Criteria:

1. Heterosexual couples in a committed relationship with a female partner aged 18-45 years and male partner aged 18 years and older attempting to conceive and seeking assisted reproduction at participating fertility clinics.
2. Couples actively trying to conceive.
3. Couples who are planning ovulation induction (OI), natural fertility optimization methods, or intrauterine insemination (IUI) should be willing to be on the study dietary supplement for at least 3 weeks before starting the next assisted reproduction cycle.Women with regular periods may initiate their fertility therapy at the start of the woman's menstrual cycle following randomization if randomization occurred within the first 10 days of the cycle, but must wait one menstrual cycle if the visit occurred after day 10 of the cycle). For women with irregular periods or amenorrhea, the male must be on the study supplement for 3 weeks prior to initiation of any ovulation induction medication (e.g., clomid, letrozole, gonadotropins).

Couples Exclusion Criteria:

1. Female partner unwilling to participate (e.g., no abstraction of her assisted fertility treatment record or unwilling to complete baseline visit).
2. Couples using donor, cryopreserved sperm, or sperm obtained via microsurgical or percutaneous epididymal sperm aspiration.
3. Couples attempting to conceive with a gestational carrier (surrogate).
4. Positive urine pregnancy test at screening.

Male Inclusion Criteria:

1. Willing to provide semen samples according to the proposed schedule at baseline, 2, 4, and 6 months of follow-up.
2. Able to complete regular study questionnaires and daily journals aimed at capturing ejaculation, sexual intercourse and lifestyle factors considered to affect male fecundity (e.g., cigarette smoking, fever, high temperature environment and other environmental exposures) and other data collection instruments (e.g., physical activity, food frequency questionnaire, stress).

Male Exclusion Criteria:

1. Age \<18 years.
2. Unwilling to abstain from use of non-study approved dietary supplements or medications containing folic acid or oral preparations containing zinc throughout the study.
3. Unwilling to abstain from use of testosterone supplementation throughout the study.
4. Diagnosis of Vitamin B12 deficiency or pernicious anemia.
5. Consuming a vegan diet.
6. A known genetic cause of male factor subfertility, including chromosomal disorders related to subfertility (e.g., Y chromosome deletions).
7. Males currently using and unwilling (or unable) to discontinue the following drugs known to interact with folic acid or interfere with the biosynthesis of folic acid will be excluded.

   1. Dihydrofolate reductase inhibitors: Trimethoprim, Triamterene, Bactrim, Iclaprim
   2. Sulfonamides: Hydrochlorothiazide (HCTZ), Metolazone, Indapamide, Lasix, Bumex, Torsemide, Chlorthalidone, Acetazolamide, Mefruside, Xipamide
   3. Sulfonylureas: Glipizide, Glyburide
   4. Cox-2 inhibitors: Celecoxib
   5. Others: Valproic acid, Probenecid, Sulfasalazine, Sumatriptan, Mafenide, Ethoxzolamide, Sulfiram, Zonisamide, Dorzolamide (optic), Dichlorphenamide, Fluorouracil, Capecitabine, Methotrexate
8. History of organ transplantation.
9. Physician diagnosed:

   1. Current poorly controlled chronic diseases such as heart disease, diabetes mellitus, hypertension, cancer, inflammatory diseases, autoimmune, thyroid disease, endocrine dysfunction, liver disease, kidney disease, or HIV/AIDS or other immune-insufficient related illnesses.
   2. Crohn's disease, celiac disease, ulcerative colitis, gastric bypass surgery, lap band surgery or history of intestinal surgery to remove a portion of small bowel. History of diseases/symptoms that require folic acid dietary supplementation, such as megaloblastic anemia, homocystinemia, and homocystinuria.
   3. History of alcohol dependency disorder and/or other drug/substance dependency in the past 180 days.
   4. History of psychoses or other mental conditions that would result in cognitive impairment and inability to participate in any part of this study including the informed consent process, as diagnosed by a physician within the past year.
10. History of vasectomy without reversal, obstructive azoospermia such as Congenital Bilateral Aplasia of Vas Deferens (CBAVD), or ejaculatory duct obstruction.
11. Known allergy to folic acid or zinc dietary supplements.

Female Exclusion Criteria:

Age \<18 or \>45 years.
B: Inclusion Criteria:

1. Referred due to infertility
2. Age: 18-50 years,
3. Non-smoking,
4. Sperm DNA Fragmentation Index \>25%

Exclusion Criteria:

1. Body mass index (BMI) ≥30,
2. FSH outside the normal range of 2-8 IU/L,g)
3. LH outside the normal range of 2-10 IU/L,
4. T \< 10nmol/L
5. Treated with antihypertensive drugs, hormones, statins, psychotropic drugs, or oral cortisone for the last six months,
6. History of anabolic steroids use,
7. Taking antioxidant supplementation the last six months.
C: Inclusion Criteria:

* Male with an age \> 18 years old
* Referred for male infertility with sperm concentration \>= 0.01 million/ml. Additionally, all men must have either sperm concentration \< 20 million/ml or \< 50% progressive motile spermatozoa or \< 12% morphological normal spermatozoa using strict criteria

Exclusion Criteria:

* Men with chronic diseases (such as diabetes mellitus, Thyroid disease, endocrine disturbances in need of treatment, malignant disease, or diseases known to interfere with VD intake or very sensitive to VD intake (such as inflammatory disease with granuloma: sarcoidoses, tuberculosis, Wegeners, vasculitis, inflammatory bowel disease (Crohn's and colitis ulcerosa etc).
* Men with present or previous malignant disease
* If there is an indication for testis biopsy and it is planned or conducted within the next 6 months
* Serum 25-hydroxy-D3 \> 50 nmol/l at the time of inclusion
* Serum Calcium ion \> 1,35 mmol/l
* Inhibin-B \< 30 pg/ml
* Intake of vitamin D above 15 ug daily
* Allergy towards vitamin D or arachidis oil (peanuts)
* Men with total or partly obstructive oligospermia and men who had vasectomy performed

Criteria for drop out:

* Abrogation of the treatment
* Newly diagnosed endocrine, calcium metabolic disease, parathyroid, thyroid, diabetes or other endocrine disease in need of treatment
* New malignant disease
* Treatment with chemotherapy, immunomodulating therapy, salazopyrin
* Oral or iv treatment with steroid hormones
* Treatment with diuretics, antihypertensive treatment, treatment the heart, calcium channel blockers
* Development of vitamin d intoxication
* If testis biopsy is performed or other surgery in the genital region during the trial
D: Inclusion Criteria:Couple

* 12 or more months of infertility (primary or secondary)
* Heterosexual
* Cohabitating and able to have regular intercourse

Male:

* ≥ 18 years of age
* At least one abnormal semen parameter on a semen analysis within the past 6 months:

  * Sperm concentration ≤15 Million/ml
  * Total motility ≤40%
  * Normal morphology (Kruger) ≤4%
  * DNA fragmentation (SCSA, DNA fragmentation index) \>25%

Female:

* ≥18 years of age and ≤40 years of age
* For women ≥ 35 years of age, evidence of normal ovarian reserve as assessed by menstrual cycle day 3 (+/-2 days) FSH ≤10 IU/L with estradiol ≤ 70 pg/mL, AMH ≥ 1.0 ng/mL, OR antral follicle count \>10 within one year prior to study initiation.
* Evidence of at least one patent fallopian tube as determined by an hysterosalpingogram or laparoscopy showing at least one patent fallopian tube or a saline infusion sonogram showing spillage of contrast material
* Regular cycles defined as ≥25 days and ≤35 days in duration
* Evidence of ovulation including biphasic basal body temperatures, positive ovulation predictor kits, or progesterone level ≥3 ng/ml.

Exclusion Criteria:

* Couple:

  * Previous sterilization procedures (vasectomy, tubal ligation). The prior procedure may affect study outcomes.
  * Planning in vitro fertilization in the next 6 months

Male:

* Sperm concentration \< 5 million/mL on screening semen analysis
* Current use of a medication or drug that would affect reproductive function or metabolism (see Appendix C for list)
* Current multivitamin or herb use (requires 1 month wash-out)
* Current serious medical illnesses, such as cancer, heart disease, or cirrhosis
* Current use of anticoagulants
* Untreated hypothyroidism
* Uncontrolled diabetes mellitus

Female:

* History of surgically or medically confirmed moderate or severe endometriosis
* Body mass index \>35 kg/m2
* Currently pregnant
* History of polycystic ovarian syndrome
* Current serious medical illnesses, such as cancer, heart disease, or cirrhosis
* History of systemic chemotherapy or pelvic radiation
* Current use of a medication or drug that would affect reproductive function or metabolism

Answer: D