Hormones

Thyroid

Despite its small size, the thyroid gland has a profound influence on our metabolism^[33]. By producing the hormones thyroxine (T4) and triiodothyronine (T3), it regulates essential processes such as energy expenditure, growth, and heat production. Thyroid abnormalities, even when subclinical, have a significant effect on metabolic health^[34], ^[35], ^[36].

TSH

TSH (thyroid-stimulating hormone) is produced by the pituitary gland in the brain and regulates the production of thyroid hormones (T4 and T3). An abnormal TSH value can indicate an underactive or overactive thyroid and therefore has direct consequences for metabolism.

The lower and upper bound of the normal range differ per laboratory. Synapse therefore uses the reference interval printed on your own lab report. If it is not printed there, we use the performing laboratory's reference table, and otherwise AML's.

In addition, two absolute bounds^[37], ^[38] apply independently of the laboratory:

A TSH below 0.1 or above 10 mU/L is clinically urgent and immediately receives the worst possible score.

FT4

T4 (thyroxine) is the main hormone produced by the thyroid gland. A portion of T4 is converted in the body into T3, the biologically more active form. Because T4 provides direct insight into thyroid function and therefore into metabolism, it is an essential biomarker for the early detection of hypo- or hyperthyroidism.

As with TSH, the lower and upper bound differ per laboratory. Synapse uses the reference interval printed on your own lab report. If it is not printed there, we use the performing laboratory's reference table, and otherwise AML's.

Sex hormones

The Sex hormones score assesses the reproductive years through five factors: the regularity of the cycle, features that fit PCOS, heavy menstrual bleeding together with the iron store, menstrual pain and premenstrual syndrome. The cycle serves as an extra vital sign: its regularity reflects the feedback loop between hypothalamus, pituitary and ovaries, and a cycle that stays irregular or runs long is an independent cardiometabolic risk marker^[1], ^[3].

The score rests on the questionnaire. No hormone assay steers the score: FSH, LH and estradiol fluctuate too much in the reproductive years, and certainly in the transition, to stage reliably. Blood values do count in two places: ferritin and hemoglobin in the heavy-bleeding factor, and the insulin resistance from the Metabolism chapter as a metabolic modulator of the PCOS features.

Each factor takes a value from one fixed ladder, higher being better. The anchors sit just below the report's colour boundaries, so every rung visibly moves one colour band.

The worst factor sets the score. Every additional orange or red factor multiplies that result by its own value as a fraction; after that, every additional yellow factor costs five points, with 0 as the floor. Rounding happens once, at the end: two factors at 49 give 49 × 0.49 = 24.01, so 24. A factor that cannot be assessed drops out entirely, from the minimum and from the count. With fewer than three assessable factors the report shows no number but the label "Incompletely assessable" with the individual factors.

The score applies to women only and is fully suppressed during pregnancy, breastfeeding or less than twelve months after childbirth. Under hormonal contraception, after removal of the uterus, after endometrial ablation or under systemic hormone replacement, her own bleeding pattern is not visible; Synapse calls this the masked route, and there the cycle factor cannot be assessed. From the age of forty, after removal of both ovaries or under hormone replacement, the transition module opens; as soon as the Menopause score opens, the Sex hormones score disappears, except on the masked route (see Menopause).

The report shows only the factors with a finding, that is below 100, and the factors that cannot be assessed, in grey with the reason. A factor whose questions were not asked does not appear.

Cycle regulation

According to FIGO a normal cycle comes every 24 to 38 days, is regular with a variation of at most 7 to 9 days and lasts up to 8 days; outside that one speaks of abnormal uterine bleeding^[1]. Secondary amenorrhoea is the absence of menstruation for 3 months or longer. The main causes of an irregular, long or absent cycle are polycystic ovary syndrome, functional hypothalamic amenorrhoea from energy deficit, weight loss, excessive training or stress, thyroid dysfunction, hyperprolactinaemia and, under forty, premature ovarian insufficiency^[2].

In the Nurses' Health Study II irregular cycles or a cycle length of 40 days or more in adulthood came with 30 to 44 % more cardiovascular disease over 24 years; hypercholesterolaemia, hypertension and type 2 diabetes together explained only 5 to 14 % of that association^[3].

Synapse reads the factor from the question on regularity and the question on average cycle length; with several findings the lowest value applies.

Under forty a period absent for more than twelve months also counts as the deepest rung; from forty an absent period stages the transition and the factor drops out.

PCOS features

Polycystic ovary syndrome, which Synapse calls PMOS in Dutch, affects up to 13 % of women of reproductive age and rests on a self-reinforcing loop of androgen excess, insulin resistance with hyperinsulinaemia and disturbed follicle maturation^[5]. The 2023 international guideline makes the diagnosis on two of three Rotterdam criteria: oligo- or anovulation, clinical or biochemical hyperandrogenism, and polycystic ovaries or an elevated AMH, after excluding thyroid disease, hyperprolactinaemia and non-classic adrenal hyperplasia. Irregular cycles plus hyperandrogenism suffice without ultrasound, and self-reported unwanted hair growth counts as clinically meaningful^[4]. The syndrome comes with insulin resistance in about two thirds, more type 2 diabetes independent of weight and an atherogenic lipid profile^[6].

This factor is a screen, not a diagnosis. It combines a cycle axis with an androgen axis from two questions: excess hair in typically male areas, and persistent acne or hair loss. The cycle axis counts only with oligo- or amenorrhoea, that is a cycle longer than 45 days or an absent period; a short, irregular or 39-to-45-day cycle is not a PCOS cycle axis. Subtly abnormal is mild excess hair, acne or hair loss alone, or the cycle axis alone; clearly abnormal is clear excess hair, or acne and hair loss together.

An insulin-resistance score in the orange or red zone (see the Metabolism chapter), prediabetes or diabetes lowers the value one rung, but only when it already stood at 74 or lower. On the masked route and from perimenopause onwards only the androgen axis counts, so without that modulator the value does not fall below 49: a long or absent cycle then belongs to the contraception or the transition and may not produce a PCOS signal. The questions on excess hair, acne and hair loss are asked only under hormonal contraception or with an irregular or absent cycle; without them the factor drops out.

Heavy bleeding and iron

Heavy menstrual bleeding is, according to FIGO, not a millilitre threshold but blood loss that affects physical, social or emotional quality of life; PALM-COEIN orders the causes, with bleeding disorders as a frequently missed category^[1]. Menstrual blood loss is the main cause of iron deficiency in women. That deficiency develops in stages: first the store (ferritin) falls, only later hemoglobin, so a normal blood count does not rule out iron deficiency without anaemia. In high-income countries about 38 % of non-pregnant women of reproductive age have such a deficiency and 13 % have anaemia^[7].

Three ferritin cut-offs are in circulation. The WHO threshold of 15 μg/L is highly specific but reaches only 59 % sensitivity; the AGA guideline uses 45 μg/L with 85 % sensitivity and 92 % specificity^[8], and the recent JAMA review 30 μg/L^[7]. In this context Synapse follows the sensitive threshold, because monthly loss raises the prior probability, and calls values between 15 and 45 depletion, not anaemia. With inflammation ferritin, an acute-phase protein, is unreliable.

The factor opens with the gate question on heavy bleeding. After No it stands at 100, except with a ferritin below 15 μg/L: then the iron axis alone applies (24, or 0 with a hemoglobin below 12 g/dL), because bleeding that is not experienced as heavy can also empty the iron store. After Yes it is the lower of two axes. The symptom axis follows the validated SAMANTA items (heaviness on the worst day, clots, duration); the iron axis reads ferritin and hemoglobin from the blood draw.

After No the tile speaks of iron only: it is titled "Iron stores: your ferritin is very low (under 15)", carries the label "Assessed on your iron stores only" and opens a factor page about the iron store, with no words about heavy bleeding. If she did report heavy bleeding, it stays the tile of this factor. The value is the same either way.

Without ferritin only the symptom axis counts, with the label "No lab results"; a hemoglobin without ferritin then does not count. Under hormonal contraception the bleeding is a withdrawal bleed, and the factor carries the label "while on hormonal contraception". After removal of the uterus, or when the period is absent, the bleeding questions are not asked and the factor drops out. If a woman on hormonal contraception reports that she no longer bleeds, the factor scores as no complaint, with that note beside it.

Menstrual pain

Primary dysmenorrhoea arises from overproduction of prostaglandins in the endometrium at the fall of progesterone before menstruation: strong contractions, raised intrauterine pressure and vasoconstriction cause ischaemia and pain. It affects 50 to 90 % of menstruating women, moderate to severe in about half, and is the main cause of short-term school and work absence in young women^[9]. Secondary dysmenorrhoea rests on pelvic pathology, above all endometriosis and adenomyosis. Endometriosis affects up to 10 % of women, is recognised on average only 5 to 12 years after the first complaints and may be suspected clinically on symptoms, examination and ultrasound^[10]. NSAIDs are first choice and over four times more effective than placebo, provided they are taken at the first cramps^[11].

The factor is the lower of a pain band on the numeric scale from 0 to 10 and an impact band from painkiller use and absenteeism. An endometriosis core symptom deepens the deepest rung: deep dyspareunia, cyclical dyschezia or dysuria, or pain that persists despite NSAIDs and hormonal treatment.

Under hormonal contraception this factor remains fully assessable, without damping: pain that persists under hormonal treatment is clinically heavier, not lighter. When the period is absent, or when the complaints question was ticked but no pain question was answered, the factor drops out.

Premenstrual syndrome

Premenstrual disorders are cyclical affective and physical complaints confined to the luteal phase that resolve after the onset of menstruation, with a symptom-free interval of at least a week^[13]. Up to 90 % of women report at least one premenstrual complaint; 20 to 30 % meet criteria for PMS and 2 to 5 % for the severe form, PMDD, with a quality of life comparable to depression and an elevated suicide risk^[12]. The complaints rest not on abnormal hormone levels but on an increased sensitivity to the normal fluctuations^[12]. The diagnosis requires prospective daily recording over at least two cycles; a retrospective questionnaire screens and triages but does not objectify cyclicity^[13]. SSRIs are first choice for affective complaints, continuous or luteal-phase^[14].

The factor reads three questions: which complaints occur in the week before menstruation, how much they weigh on daily functioning, and whether they disappear after the onset of menstruation. Core affective complaints are mood swings, irritability, low mood and anxiety or tension.

If the woman does not know whether the complaints disappear once menstruation starts, or if they do not, the factor stays at 74 with the label "Pattern unclear", the advice of a symptom diary follows: complaints present throughout the cycle that worsen premenstrually point to an underlying disorder, which the mental domain follows up. Under hormonal contraception the factor carries, like heavy bleeding, the label "while on hormonal contraception": the contraception damps the hormonal fluctuation that drives PMS.

Menopause

The Menopause score assesses the transition through six factors: hot flushes and night sweats, physical complaints, sexual desire, vaginal and bladder complaints, anxiety and mood. Four of them come directly from the transition module, each of whose items is scored from 0 to 3 (absent, occasional and not bothersome, often and bothersome, very often and interrupting activities). Anxiety and mood are not asked again but derived from the mental questionnaires everyone completes, the GAD-7 and the derived PHQ-9.

The transition module starts from the Greene Climacteric Scale, a validated scale of 21 items. Synapse deliberately departs from it on five points. The scale's anxiety questions are replaced by the GAD-7 and its depression questions by the existing depression score, a derived PHQ-9. The palpitations item under anxiety is new and not part of the scale. The four vaginal and bladder complaints are not part of the scale either: that extension comes from practice, not from the validation literature. The sleep item of the anxiety subscale is not asked separately but derived from the sleep domain score, with the weight the scale gives it. The result is therefore not a Greene scale total and must not be compared with its norms: it is a repeatable measure of how much burden the woman experiences, to follow over time and to open a conversation.

Which score the report shows depends on the route. On the bleeding route Synapse stages clinically according to STRAW+10, without any blood value: a cycle that changed in the past year counts as perimenopause; from forty, so does a period absent for more than 3 months, and more than 12 months counts as postmenopause. From perimenopause onwards Menopause then replaces the Sex hormones score. After removal of both ovaries, the surgical route, the woman is postmenopausal at once and Menopause applies. On the masked route the stage cannot be determined from the cycle: there Menopause opens from 45, or from 40 as soon as hot flushes or night sweats are often and bothersome or worse, and the Sex hormones score stays beside it. That also holds under systemic hormone replacement; if a factor stands at 49 or lower there, the doctor's report asks for the treatment to be evaluated. Without the transition module Sex hormones remains the only score.

The four factors from the transition module share one ladder that looks at the highest answer and at how many answers sit at that level. One very severe symptom therefore weighs more than several mild ones, in line with the finding that a single very severe item by itself already indicates a need for treatment. There is deliberately no sum score over the items.

The worst factor sets the score, with the same combination rule as for Sex hormones: each additional orange or red factor multiplies the result by its own value as a fraction, after which each additional yellow factor costs five points. With fewer than three assessable factors the report shows no number but the individual factors.

In the transition, cycle regulation, bleeding, pain and PMS no longer count in a score. Under Menopause the report shows the six factors below as tiles, by the same rule as under Sex hormones: only the factors with a finding and the factors that cannot be assessed. Under each factor from the transition module the report lists the answers it was read from; a complaint that is absent does not appear. The cycle factor does not appear in the transition, not even as a grey tile: not under Menopause, and on the masked route not under Sex hormones either. If the cycle rung is 49 or lower, the PCOS features tile also appears, fed by the androgen axis alone; it does not count in the Menopause score.

Hot flushes and night sweats

Hot flushes and night sweats arise from oestrogen withdrawal in the hypothalamus: KNDy neurons releasing neurokinin B become overactive and narrow the thermoneutral zone, so a small rise in core temperature triggers a full heat-dissipation response; that mechanism is also the basis of the neurokinin 3 receptor antagonists^[17]. Up to 80 % of women experience them. In the SWAN cohort frequent symptoms lasted a median of 7.4 years, more than 11 years when they started before or in early perimenopause and a median of 3.4 years with a postmenopausal start^[16].

The symptoms fragment sleep and lower the threshold for irritability and low mood, and frequent or early-onset flushes are regarded as a possible marker of cardiovascular risk^[15]. Hormone therapy is the most effective treatment, reducing flushes by about 75 %, and has a favourable benefit-risk balance in women under 60 or within ten years of their last period without contraindications^[15]. Non-hormonal options with evidence are fezolinetant, SSRIs or SNRIs, gabapentin, cognitive behavioural therapy and clinical hypnosis; exercise, yoga, cooling techniques and avoiding triggers do not reduce frequency^[17].

Synapse reads the factor from the two items hot flushes and night sweats.

Physical complaints

Muscle and joint pain is the most convincing physical complaint of the transition: more than 70 % of women experience musculoskeletal symptoms during the transition and about a quarter are limited by them. Oestrogen receptors in cartilage, synovium, muscle and tendon explain the link; the cluster of arthralgia, muscle and bone loss and accelerated osteoarthritis has recently been named the musculoskeletal syndrome of menopause^[18]. Headache and migraine often worsen in perimenopause because of fluctuating oestrogen; migraine without aura usually improves after menopause, migraine with aura more often persists^[20].

In the WHI trial oestrogen alone produced a modest but sustained reduction in joint pain after one year, but hormone therapy is not an indication for joint pain in itself^[19]. Resistance training, sufficient protein and weight management are the first choice for muscles, bones and joints^[18]. Tingling and a feeling of tension are the least specific items: new complaints in this age group call for ruling out inflammatory arthritis, hypothyroidism, vitamin D deficiency, carpal tunnel syndrome and polymyalgia.

Synapse reads the factor from the gate question and the four items headache, muscle and joint pain, numbness or tingling, and feeling of tension or pressure.

Sexual desire

In the SWAN cohort desire, arousal and satisfaction were most strongly related to relationship factors, the importance the woman attached to sex, her attitude to ageing and vaginal dryness; early perimenopause itself mainly added pain with intercourse^[21]. Among 2,020 Australian women aged 40 to 65, 69 % reported low desire, 40 % distress and 32 % both, the definition of hypoactive sexual desire dysfunction; vaginal dryness, pain with intercourse, depressive symptoms and psychotropic medication were associated with it, hot flushes were not^[22].

What separates it from simply less desire is the distress. Treat the modifiable causes first: local oestrogen for dryness or pain, attention to mood, sleep and medication, and psychosexual or couples counselling. Transdermal testosterone has a moderate effect in postmenopausal women with a desire disorder, at a dose restoring premenopausal levels and with monitoring of blood levels; a blood level does not make the diagnosis^[23].

Synapse reads the factor from the single item less interest in sex; with one item the stacked rungs are unreachable and 49 is the lowest value.

Vaginal and bladder complaints

The genitourinary syndrome of menopause comprises dryness, burning and irritation of vulva and vagina, pain with intercourse, and urinary complaints such as urgency, dysuria and recurrent urinary tract infections. Oestrogen deficiency makes the epithelium thin and fragile, raises vaginal pH and displaces the lactobacilli; unlike vasomotor symptoms the course is chronic and progressive without treatment^[24]. The syndrome is systematically undertreated: in a systematic review of 27 studies the prevalence of symptoms ranged from 13 to 87 % while only 13 to 78 % used a specific treatment^[25].

Moisturisers and lubricants suffice for mild complaints. For moderate to severe complaints low-dose vaginal oestrogen is the most effective option: in the Cochrane review of 30 studies all forms improved symptoms compared with placebo, with no difference between them^[26]. Systemic absorption is minimal, a progestogen is not needed and vaginal oestrogen also reduces recurrent urinary tract infections^[24]. Postmenopausal bleeding or a suspicious lesion calls for referral.

Synapse reads the factor from the four items dryness or burning, irritation or itching, recurrent infections, and bladder complaints, which are put without a gate question to every woman in the transition module. This domain is not part of the Greene scale; the classification is our own work, because no validated system of severity bands exists for this domain.

Anxiety

In the SWAN cohort of 2,956 women, those with low anxiety before the transition had higher odds of high anxiety symptoms in early and late perimenopause and after, independent of life events, financial strain and hot flushes; women already anxious stayed anxious without a stage-specific peak^[27]. Palpitations, sweating and a pounding heart are symptoms that anxiety, panic and hot flushes share, and somatic items also overlap with thyroid disease.

The GAD-7 measures generalised anxiety symptoms over two weeks with bands of 5, 10 and 15 for mild, moderate and severe symptoms; at a cut-off of 10 the original validation found a sensitivity of 89 % and a specificity of 82 %^[28]. In a meta-analysis of 12 samples cut-offs of 7 to 10 were similarly accurate, and the scale is less reliable for panic and social anxiety^[29]. A positive score is a prompt for a conversation, not a diagnosis; cognitive behavioural therapy is first choice and SSRIs or SNRIs also reduce hot flushes.

Synapse reads the factor from the GAD-7 of the mental domain. Up to 3 points for sleep are added: the anxiety subscale of the Greene scale holds one sleep item, worth 3 of its 63 points, and Synapse derives that item from the sleep domain score as (100 − sleep domain score) / 100 × 3. The palpitations item lowers the factor one rung when it occurs very often; often and bothersome does not change the value. If the first mental screening is favourable, the follow-up questions are not asked and the GAD-7 counts as 0.

Mood

The transition is a window of vulnerability for mood. In the Penn Ovarian Aging Study the odds of depressive symptoms in women without a history were more than four times higher during the transition than before it, and those of a depressive disorder two and a half times, linked to the fluctuating hormone levels^[31]. In SWAN the odds of a depressive episode were two to four times higher in peri- and early postmenopause, independent of hot flushes and hormone levels^[32]. The strongest predictor remains a previous depression.

The guideline on perimenopausal depression recommends establishing the menopausal stage and ruling out thyroid disease, anaemia, sleep apnoea, substance use and bipolar disorder; antidepressants and psychotherapy are first choice, and oestrogen has an antidepressant effect in perimenopausal women with hot flushes but is not approved for it^[30]. Any answer above No to the question on dark thoughts also activates the safety protocol of the mental domain.

Synapse reads the factor from the existing depression score: the derived PHQ-9 passes through the conversion to a percentage where higher is better, and that percentage lands on the matching ladder rung. Because the conversion places the PHQ-9 severity limits 4, 9 and 14 at 75, 50 and 25 %, the rungs follow the published bands. If the first mental screening is favourable, the PHQ-9 counts as 0.

Developed and reviewed with the Synapse medical advisory board.

References

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Put it into practice

Hormones

• Cortisol and insulin resistance
• Hunger hormones
• Nutrition and the thyroid
• Thyroid and stress
• Thyroid hormones

Biomarkers in this domain

• TSH
• FT4
• Cortisol