A case study presented by Angela Hywood at the Integria Practitioner Systems Endocrinology: An Integrative Approach Symposium.

Like several other female reproductive conditions, endometriosis is associated with elevated oestrogen or excess tissue oestrogen exposure in women. This case focusses on metabolism of hormones, specifically adequate clearance of oestrogen to correct the length of follicular and luteal phases to support fertility. Secondary focuses included reducing inflammation and naturally managing attention-deficit/hyperactivity disorder (ADHD), so the client could come off Ritalin ahead of trying to conceive. This case also demonstrates that methylenetetrahydrofolate reductase (MTHFR) gene testing should be emphasised in preconception workup, especially in endometriosis sufferers.

Therapeutic goals to support healthy oestrogen balance should focus on:

1. Supporting phase I conversion of oestrogens to 2-OH, rather than 4- or 16-OH
2. Supporting phase II conjugation of hydroxyoestrogens
3. Neutralising oxidative oestrogen metabolites by enhancing the activity of NQO1, NQO2 and nuclear factor erythroid 2-related 2 (Nrf2)
4. Reducing excessive oestrogen synthesis by inhibiting aromatase
5. Supporting the oestrobolome

Figure 1. The Metabolism of Oestrogen^1,2

* To learn about oestrogen metabolism, refer to:

• Phytotherapist’s Perspective No. 257 Herbs to Support Oestrogen Metabolism
• Systems Endocrinology: An Integrative Approach: SYM24 S5: Unravelling Complex Women's Health Cases through the Lifespan - Angela Hywood
• Unveiling the Hidden Pathways: A Whole-body Approach for Female Reproductive Health: Session 1: A Whole-Body Approach to Endometriosis with Emma Van Den Driest

Initial Consultation

A 34-year-old female with endometriosis presented with the desire to try to conceive shortly after her upcoming marriage. She also wished to clear her hormonal acne before her wedding.

Her endometriosis history was complex. She had 2 laparoscopy surgeries (2016 and 2019). Within 12 months of the 2019 surgery, she developed 2 large endometriomas that were surgically removed. She lost her left ovary in the surgery. Her Fallopian tubes were intact and patent.

At the end of 2019, she had eggs preserved with IVF Australia. Subsequently, a low anti-Müllerian hormone (AMH) level was found and she underwent 2 rounds of stimulation for cryopreservation from which 6 eggs were stored, constituting a poor outcome.

She had her Mirena intrauterine device (IUD) removed after a large loop excision of the transformation zone (LLETZ) procedure in mid-2021 for cervical dysplasia (irregular Pap smear). Since 2021, her Pap smears were normal but she has had a gradual increase in endometriosis symptoms.

Her menstrual cycle was regular but short. She bled for 5 days every 21 days. She experienced pain from ovulation; pain throughout the cycle; and pain before the onset of menstrual flow, typical of endometriosis. For her painful menstruation, she relied on 2 x ibuprofen every 6 hours.

She reported also having constant severe lower back pain (every day, all cycle), cyclical urinary urgency, significant constipation, random night sweats (that mostly occurred before her period), and premenstrual syndrome (PMS) [i.e. severe mood swings and brain fog].

A tertiary level pelvic ultrasound showed mobile pelvic organs with significant tenderness around both ovaries. The left ovary was very small with only a single antral follicle.

Anxiety, panic attacks, ADHD (Rx Ritalin), high stress levels, irritability, mood swings, and brain fog were reported in her mental history.

Chronic constipation, flatulence, reflux/heartburn, and irritable bowel syndrome (IBS) were noted.

At the time of her first visit, she had been taking the following supplements and medications:

• 1 x OTC prenatal supplement
• 1 x OTC probiotic
• 1 x magnesium tablet
• 1 x vitamin D (1000 IU)
• 4 x Ritalin (10 to 50 mg)
• 2 x ibuprofen every 6 hours as required (for painful menstruation)

Intake Pathology

At intake, her active vitamin B6, vitamin B12, active B12, serum folate, and full blood count (FBC) parameters were all within normal limits, though her vitamin B12 was deemed suboptimal low (246 pmol/L). Thyroid-stimulating hormone (TSH) was 0.95 mU/L. Her iron studies revealed low transferrin (23 µmol/L) though her iron, saturation and ferritin were normal. High C-reactive protein (CRP) [5 mg/L] was found. Her AMH, a marker of ovarian follicle reserve was low normal for age (10th to 50th percentile) [13.8 pmol/L].

NB: as a positive acute phase reactant, ferritin can be elevated with an increased inflammatory load; however, since saturation was within normal limits this was not a concern.

Initial Prescription

The initial prescription was aimed at providing baseline preconception care, optimising fertility, managing endometriosis, and supporting hormonal skin health.

Further investigations included a:

• MTHFR gene test (buccal swab)
• Cytokine panel
• Dried urine test for comprehensive hormones (DUTCH) test

Prescription

• Prenatal & Pregnancy Multivitamin Tablets, 2 daily; containing levomefolate calcium 309.6 mcg equiv. levomefolic acid 250 mcg, iodine (as potassium iodide) 140 mcg, phytomenadione 25 mcg, menaquinone-7 (MK-7) 25 mcg, colecalciferol 12.5 mcg, riboflavin sodium phosphate 10 mg equiv. riboflavin 7.3 mg, pyridoxal 5-phosphate (P5P) monohydrate 7.84 mg equiv. pyridoxine 5 mg, pyridoxine hydrochloride 6.08 mg equiv. pyridoxine 5 mg, mecobalamin (co-methylcobalamin) 250 mcg, choline bitartrate 243.1 mg equiv. choline 100 mg, selenomethionine 93.1 mcg, equiv. selenium 37.5 mcg, zinc amino acid chelate 25 mg equiv. zinc 5 mg, thiamine hydrochloride 12.5 mg equiv. thiamine 11.15 mg, iron (II) glycinate 43.83 mg equiv. iron 12 mg, biotin 150 mcg, inositol 25 mg, nicotinamide 10 mg, calcium pantothenate 7.5 mg equiv. pantothenic acid 6.9 mg, ascorbic acid 75.5 mg, chromium nicotinate 208.3 mcg equiv. chromium 25 mcg, manganese amino acid chelate 12.5 mg equiv. manganese 1.25 mg, molybdenum trioxide 37.47 mcg equiv. molybdenum 25 mcg, lutein 3 mg, zeaxanthin 600 mcg
• Concentrated Fish Oil Capsules, 2 daily; containing, concentrated Omega-3 triglycerides – fish 1.0 g, equiv. eicosapentaenoic acid (EPA) 400 mg, equiv. docosahexaenoic acid (DHA) 200 mg
• Learning & Memory Magnesium Powder, 1 scoop (6 g) twice daily; containing Bacopa monnieri (Bacopa) extract 225 mg derived from minimum whole plant dry 4.5 g standarised to key bacosides calculated as bacoside A 52.6 mg, Crocus sativus (Saffron) extract 15 mg derived from stigma dry 45 mg, acetyl levocarnitine hydrochloride 1.18 g, magnesium citrate 1.23 g equiv. magnesium 200 mg, calcium folinate 347 ug equiv. folinic acid 250 ug, zinc amino acid chelate 25 mg equiv. zinc 5 mg, P5P monohydrate 7.8 mg equiv. pyridoxine (vitamin B6) 5 mg, mecobalamin 500 ug, nicotinamide 17.5 mg, tyrosine 1 g
• Women's Flora Probiotic, 1 daily; containing 6.3 billion CFU Lactobacillus spp.
• Phase II Liver Formula Powder, 1 tsp (4 g) twice daily; containing Brassica oleracea var. italica (Broccoli Seed) extract 150 mg derived from minimum seed dry 1.5 g standardised to glucoraphanin 19.5 mg, Brassica oleracea var. italica (Broccoli Sprout) extract 200 mg derived from sprout fresh 1 g, Curcuma longa (Turmeric) extract 85 mg derived from minimum rhizome dry 2 g equiv. curcuminoids 76.5 mg, glutamine 750 mg, glycine 500 mg, taurine 500 mg, cysteine hydrochloride 181 mg equiv. cysteine 125 mg, methionine 125 mg, choline bitartrate 250 mg, inositol 200 mg, potassium sulfate 150 mg equiv. potassium 67 mg
• DHA + for Brain Health Capsules, 1 twice daily; containing concentrated fish omega-3 triglycerides 978 mg equiv. to DHA 450 mg and EPA 98 mg, choline bitartrate 348.9 mg equiv. choline 143.5 mg, cholecalciferol 6.25 mcg, equiv. vitamin D3 250 IU
• Endometriosis Support Tablets, 2 twice daily; Angelica polymorpha (Dong Quai) extract 118 mg derived from root dry 826 mg, Paeonia lactiflora (Paeonia) extract 206 mg derived from root dry 824 mg, Alchemilla vulgaris (Ladies Mantle) extract 1.3 mL derived from herb dry 650 mg, Calendula officinalis (Calendula) extract 0.8 mL derived from flower dry 400 mg

Follow Up – 6 Weeks Later

The client was feeling much better. Her skin had significantly cleared up and was delighted about this pre-wedding. Her bowels were now regular, with help of fibre education. The initial prescription enabled her to reduce Ritalin from 4 to 2 per day.

Her mood was a lot better, with less “down” moments reported. Her menstrual flow was red and fresh, less dark and congestive. She had notably less pain, including less back pain. She halved her ibuprofen use.

Pathology Results

The MTHFR gene mutation test: MTHFR compound heterozygous. Heterozygous for the A1298C mutation and heterozygous for the C677T mutation.

Cytokine panel results: borderline elevated interleukin (IL)-8 (24.4 pg/mL).

DUTCH test results: progesterone and testosterone were within normal limits but high oestradiol (E2) [6.0 ng/mg]. Her 24-hour free cortisol was very high (366 ng/mg) and her metabolised cortisol (the best marker of overall cortisol production) was borderline low (2829 ng/mg). Thus, the DUTCH test served as confirmation of poor methylation and poor clearance of E2. It suggested that cortisol clearance was sluggish, because her free cortisol levels were high despite low overall production.

Prescription

• The previous prescription was continued, except
• Added Methylation Support Tablets, 2 daily; Camellia sinensis (Green Tea) extract 160 mg derived from minimum leaf dry 4 g standardised to contain polyphenols calculated as gallic acid 80 mg, choline bitartrate 300 mg, levomefolate calcium 433 mcg equiv. levomefolic acid 400 mcg, mecobalamin (co-methylcobalamin) (methyl vitamin B12) 1 mg, riboflavin sodium phosphate 10 mg equiv. riboflavin (vitamin B2) 7.3 mg, P5P monohydrate 62.7 mg equiv. pyridoxine (vitamin B6) 40 mg
• Removed DHA + for Brain Health Capsules since Methylation Support Tablets contained choline

Follow Up – 6 Weeks Later

Client got married last month and revealed that with her next ovulation, she will be actively trying to conceive. She reports seeing abundant fertile mucus aligned with ovulation predictor kit peak fertility days. She suspects another cyst on R side ovary, very sore, DDx endometrioma. Her constipation had been worse since the suspected ovary cyst. Her skin had been very clear with no breakouts before her last period, with which she experienced dysmenorrhoea and back pain (2-3/10) and took only 1 ibuprofen. Her last cycle was lengthened from 21 to 24 days, a huge positive shift. Very mild PMS with only 1 day of feeling a little teary.

She said her brain feels clear and her focus is good. She is now off Ritalin and immensely pleased with her success. Her goal was to be off Ritalin when trying to conceive and throughout pregnancy. Her mood is consistent and bright with very few down days.

Prescription (Actively Trying to Conceive)

• The previous prescription was continued, except
• Removed Phase II Liver Formula Powder

Follow Up – 10 Weeks Later

Her last 2 cycles were 24 and 26 days, respectively. She had been continuing to see abundant fertile mucus aligned with ovulation predictor kit and trying to conceive both cycles. No further ovarian cyst pain. Her bowels were regular and she passed 1-2 healthy stools per day. Her skin continued to be very clear. During her last period, dysmenorrhoea and back pain were 2/10, no ibuprofen required. Moreover, she had a positive pregnancy test.

Her cognition was excellent and mood was great.

Prescription (Pregnant)

• The previous prescription was continued, except
• Swapped Learning & Memory Magnesium Powder for Calming Magnesium Powder, 12 g per day; Withania somnifera (Withania) extract 150 mg derived from minimum root dry 1.5 g standardised to contain withanolides 3.75 mg, magnesium citrate 1.86 g equiv. magnesium 300 mg, potassium phosphate dibasic 222.7 mg equiv. potassium 100 mg, glycine 1.5 g, glutamine 1.5 g, taurine 1.5 g, ascorbic acid (vitamin C) 250 mg, calcium pantothenate 50 mg equiv. pantothenic acid (vitamin B5) 45.8 mg, P5P monohydrate 78.4 mg equiv. pyridoxine (vitamin B6) 50 mg, zinc citrate dihydrate 46.7 mg equiv. zinc 15 mg

Clinical Reflections

Preconception care, especially in complex cases, often requires extensive but necessary prescriptions. Testing is often justified to inform clinical decision making and drive clinical compliance when prescriptions are comprised of multiple moving parts. Supporting hormone (i.e. oestrogen and cortisol) metabolism and clearance, ADHD and methylation, and treating these not as separate but rather as part of the overall clinical picture, informed this prescription. This approach was foundational to reducing her inflammation and promoting hormonal balance, wellbeing, fertility, and planned pregnancy.

* For further information, purchase/access the Integria Practitioner Systems Endocrinology: An Integrative Approach Symposium, available from https://practitioner.integria.com/events/systems-endocrinology-an-integrative-approach

References

1. Integria Practitioner. Systems endocrinology: an integrative approach [symposium]. Eight Mile Plains (AU): Integria Healthcare; 2024 [cited 2024 Sep 20]. Available from: https://practitioner.integria.com/

2. MediHerb. Herbs to support oestrogen metabolism. Phytotherapist’s Perspective. 2023;257. Available from: https://practitioner.integria.com/