The science
The Science Behind the Approach
Your biology doesn’t operate in separate departments. Neither should our understanding of it.
Hormones influence the brain. The gut communicates with the nervous system. Sleep affects metabolism. Stress can influence digestion, immune function and hormonal regulation.
And a woman’s experiences, environment and history can have measurable relationships with her physiology.
These connections are not simply philosophical ideas. They are subjects of decades of scientific investigation.
The evidence behind This Is Perimenopause
Nearly 300 scientific references underpin the book. Here are 20 of them.
A concise evidence snapshot spanning reproductive endocrinology, neuroscience, hormone therapy, gut–brain medicine, metabolic health, stress physiology and the biopsychosocial determinants of health.
These studies inform how we understand the body’s interconnected systems. They include trials, reviews, observational research, experimental work and meta-analyses, each with its own level of certainty. They are the scientific foundations of the approach, not direct trials of The Holland Clinic’s complete method.
Hormone science
Design & population
Expert narrative review; no study population.
What researchers found
Comprehensive review of the endocrinology of the menopausal transition.
Why it matters in perimenopause care
Foundational reference for understanding perimenopause as an endocrine state in its own right rather than simply early menopause.
Full citation
Prior JC. Perimenopause: the complex endocrinology of the menopausal transition. Endocr Rev. 1998;19(4):397-428.
DOI: 10.1210/edrv.19.4.0341Design & population
6-month observational study; 11 perimenopausal women compared with reproductive-age and other groups.
What researchers found
Perimenopause showed shorter cycles, higher FSH/LH and estrogen activity, and reduced luteal progesterone; changes were observable from the early 40s.
Why it matters in perimenopause care
Direct hormonal measurement shows that perimenopause is not simply a state of estrogen deficiency.
Full citation
Santoro N, Brown JR, Adel T, Skurnick JH. Characterization of reproductive hormonal dynamics in the perimenopause. J Clin Endocrinol Metab. 1996;81(4):1495-1501.
DOI: 10.1210/jcem.81.4.8636357Design & population
Narrative review and clinical argument.
What researchers found
Describes erratic, often higher estradiol alongside lower progesterone in symptomatic perimenopause and argues that women are frequently counselled and treated inaccurately.
Why it matters in perimenopause care
Names the clinical gap in perimenopause care and challenges a simple estrogen-deficiency model.
Full citation
Prior JC. Progesterone for symptomatic perimenopause treatment - progesterone politics, physiology and potential for perimenopause. Facts Views Vis Obgyn. 2011;3(2):109-120.
Design & population
Phase III double-blind randomised placebo-controlled trial; 4 months; 189 perimenopausal women aged 35-58.
What researchers found
Primary vasomotor score did not significantly differ from placebo. Progesterone users reported fewer night sweats, better sleep and less interference with daily life; no serious adverse events.
Why it matters in perimenopause care
A placebo-controlled trial specifically testing oral micronised progesterone in perimenopausal women.
Full citation
Prior JC, Cameron A, Fung M, Hitchcock CL, Janssen P, Lee T, et al. Oral micronized progesterone for perimenopausal night sweats and hot flushes: a Phase III Canada-wide randomized placebo-controlled 4 month trial. Sci Rep. 2023;13(1):9082.
DOI: 10.1038/s41598-023-35826-wNeuroscience and mood
Design & population
Invited review; no study population.
What researchers found
Describes perimenopause as a neurological transition and the uncoupling of estrogen-receptor signalling from brain bioenergetics.
Why it matters in perimenopause care
Helps explain why brain fog, sleep disruption and mood change can be integral features of the transition.
Full citation
Brinton RD, Yao J, Yin F, Mack WJ, Cadenas E. Perimenopause as a neurological transition state. Nat Rev Endocrinol. 2015;11(7):393-405.
DOI: 10.1038/nrendo.2015.82Design & population
8-week observational study; 50 unmedicated perimenopausal women with mild-moderate depressive symptoms.
What researchers found
Greater estradiol variability and absence of progesterone levels consistent with ovulation were independently associated with higher depressive symptom scores.
Why it matters in perimenopause care
Links mood symptoms with hormonal dysregulation rather than assuming they arise only from vasomotor symptom burden.
Full citation
Joffe H, de Wit A, Coborn J, Crawford S, Freeman M, Wiley A, et al. Impact of Estradiol Variability and Progesterone on Mood in Perimenopausal Women With Depressive Symptoms. J Clin Endocrinol Metab. 2020;105(3):e642-e650.
DOI: 10.1210/clinem/dgz181Hormone therapy and progestogens
Design & population
Systematic review and meta-analysis of observational studies; 86,881 postmenopausal women.
What researchers found
Progesterone with estrogen was associated with lower breast-cancer risk than synthetic progestins with estrogen (RR 0.67, 95% CI 0.55-0.81).
Why it matters in perimenopause care
Shows why body-identical progesterone and synthetic progestins should not automatically be treated as equivalent.
Full citation
Asi N, Mohammed K, Haydour Q, Gionfriddo MR, Vargas OL, Prokop LJ, et al. Progesterone vs. synthetic progestins and the risk of breast cancer: a systematic review and meta-analysis. Syst Rev. 2016;5(1):121.
DOI: 10.1186/s13643-016-0294-5Design & population
Prospective E3N cohort; 80,377 postmenopausal women; 2,354 invasive breast cancers.
What researchers found
Breast-cancer risk differed according to the progestogen combined with estrogen; estrogen plus progesterone showed a different risk profile from several other combinations.
Why it matters in perimenopause care
Shows that hormone-therapy risk depends partly on the specific progestogen used.
Full citation
Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008;107(1):103-111.
DOI: 10.1007/s10549-007-9523-xDesign & population
Long-term follow-up of two placebo-controlled randomised trials; 27,347 postmenopausal women; more than 20 years median follow-up.
What researchers found
CEE plus medroxyprogesterone acetate was associated with higher breast-cancer incidence; CEE alone after hysterectomy was associated with lower incidence and mortality.
Why it matters in perimenopause care
Clarifies the WHI evidence by showing that outcomes differed between specific hormone regimens.
Full citation
Chlebowski RT, Anderson GL, Aragaki AK, Manson JE, Stefanick ML, Pan K, et al. Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women's Health Initiative Randomized Clinical Trials. JAMA. 2020;324(4):369-380.
DOI: 10.1001/jama.2020.9482Design & population
Review; no study population.
What researchers found
Documents major differences among progestogens in structure, metabolism, receptor affinity, potency and clinical effects.
Why it matters in perimenopause care
Establishes that natural progesterone and synthetic progestins cannot be assumed to have a single class effect.
Full citation
Stanczyk FZ, Hapgood JP, Winer S, Mishell DR. Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects. Endocr Rev. 2013;34(2):171-208.
DOI: 10.1210/er.2012-1008Gut–brain medicine
Design & population
Authoritative review; no study population.
What researchers found
Reviews bidirectional brain-gut-microbiome interactions and the evidence and limits surrounding microbiome causality.
Why it matters in perimenopause care
Provides an evidence-based foundation for considering gut-brain communication while remaining clear about current scientific limits.
Full citation
Mayer EA, Nance K, Chen S. The Gut-Brain Axis. Annu Rev Med. 2022;73:439-453.
DOI: 10.1146/annurev-med-042320-014032Design & population
Review; no study population.
What researchers found
Reviews the intestinal barrier and conditions associated with increased permeability, while emphasising limitations in definitions, measurement and clinical significance.
Why it matters in perimenopause care
Supports intestinal permeability as a legitimate research target while keeping the limits of the evidence explicit.
Full citation
Bischoff SC, Barbara G, Buurman W, Ockhuizen T, Schulzke JD, Serino M, et al. Intestinal permeability - a new target for disease prevention and therapy. BMC Gastroenterol. 2014;14:189.
DOI: 10.1186/s12876-014-0189-7Design & population
Experimental human studies; 23 healthy volunteers, then 13; positive comparator and pharmacological blockade.
What researchers found
Acute psychological stress increased small-intestinal permeability; CRH reproduced the effect and mast-cell stabilisation blocked it.
Why it matters in perimenopause care
Demonstrates in humans that acute psychological stress can increase gut permeability.
Full citation
Vanuytsel T, van Wanrooy S, Vanheel H, Vanormelingen C, Verschueren S, Houben E, et al. Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut. 2014;63(8):1293-1299.
DOI: 10.1136/gutjnl-2013-305690Metabolic health
Design & population
Review; no study population.
What researchers found
Defines metabolic flexibility as the capacity to adapt fuel use to changing metabolic demand and reviews metabolic inflexibility in obesity and type 2 diabetes.
Why it matters in perimenopause care
Provides the reference framework for metabolic flexibility underpinning the metabolic-health component of the book.
Full citation
Goodpaster BH, Sparks LM. Metabolic Flexibility in Health and Disease. Cell Metab. 2017;25(5):1027-1036.
DOI: 10.1016/j.cmet.2017.04.015Design & population
Review of rodent and human literature.
What researchers found
Reviews estrogen-receptor effects on appetite, energy expenditure, fat distribution, insulin sensitivity, inflammation and insulin secretion.
Why it matters in perimenopause care
Explains why changing estrogen signalling can influence metabolic health and why metabolic change is not simply a matter of willpower.
Full citation
Mauvais-Jarvis F, Clegg DJ, Hevener AL. The role of estrogens in control of energy balance and glucose homeostasis. Endocr Rev. 2013;34(3):309-338.
DOI: 10.1210/er.2012-1055Stress physiology and the biopsychosocial model
Design & population
Cross-sectional ACE Study; 9,508 adults.
What researchers found
A graded relationship was found between adverse childhood experiences and later health-risk behaviours and disease.
Why it matters in perimenopause care
Established the association between childhood adversity and adult health, supporting a biopsychosocial view of health.
Full citation
Felitti VJ, Anda RF, Nordenberg D, Williamson DF, Spitz AM, Edwards V, et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults: the ACE Study. Am J Prev Med. 1998;14(4):245-258.
DOI: 10.1016/S0749-3797(98)00017-8Design & population
Review; no study population.
What researchers found
Reviews enduring nervous, endocrine and immune changes associated with childhood adversity, including HPA-axis activation and inflammation.
Why it matters in perimenopause care
Provides biological mechanisms linking lived experience and chronic stress with later health.
Full citation
Danese A, McEwen BS. Adverse childhood experiences, allostasis, allostatic load, and age-related disease. Physiol Behav. 2012;106(1):29-39.
DOI: 10.1016/j.physbeh.2011.08.019Design & population
Systematic review and meta-analysis; 37 studies; 253,719 participants; 23 health outcomes.
What researchers found
Four or more adverse childhood experiences were associated with increased risk across all 23 outcomes, with effect sizes varying substantially by outcome.
Why it matters in perimenopause care
Quantifies the relationship between childhood adversity and adult health across a large pooled population.
Full citation
Hughes K, Bellis MA, Hardcastle KA, Sethi D, Butchart A, Mikton C, et al. The effect of multiple adverse childhood experiences on health: a systematic review and meta-analysis. Lancet Public Health. 2017;2(8):e356-e366.
DOI: 10.1016/S2468-2667(17)30118-4Models of care and life history
Design & population
Review; first paper in the Lancet Series on menopause.
What researchers found
Proposes an empowerment model in which the patient is an expert in her own condition and an active partner in care.
Why it matters in perimenopause care
A current high-profile model for menopause care built around knowledge, agency and partnership.
Full citation
Hickey M, LaCroix AZ, Doust J, Mishra GD, Sivakami M, Garlick D, et al. An empowerment model for managing menopause. Lancet. 2024;403(10430):947-957.
DOI: 10.1016/S0140-6736(23)02799-XDesign & population
Evolutionary hypothesis paper; no study population.
What researchers found
Proposes that long postmenopausal lifespans evolved alongside grandmothering and food sharing.
Why it matters in perimenopause care
Reframes the post-reproductive years as an evolved feature of human life history rather than simply decline.
Full citation
Hawkes K, O'Connell JF, Jones NG, Alvarez H, Charnov EL. Grandmothering, menopause, and the evolution of human life histories. Proc Natl Acad Sci U S A. 1998;95(3):1336-1339.
DOI: 10.1073/pnas.95.3.1336