PCOS

PCOS is strongly correlated with hyperlipidemia, hypertension, hepatic steatosis, and glucose intolerance/ insulin resistance. Recognizing xanthine as correlating strongly with metabolic syndrome, we may conclude that PCOS is a disorder including excess xanthine. Correlation between more severe PCOS and more elevated uric acid levels has been demonstrated PMID 30359269. IMG

Tamoxifen is an estrogen blocker that shares inosine-similarity with fluoxetine.  It has clear neurocognitive effects PMID 32822707 and has been used therapeutically in cases of severe mental illness PMID 18058448.

Structural similarity to duloxetine, connected to chlorpromazine by apparent clinical effect, the combination of chlorpromazine and tamoxifen provide additive benefits in cancer treatment PMID 19584708

Clomiphene has traditionally been used to induce ovulation in patients with PCOS, but an open label trial demonstrated similar efficacy to tamoxifen PMID 15726910, which is much more readily available. IMG

There are fluctuations in sodium (controlled by Io,i) and uric acid throughout the normal menstrual cycle PMID 23562957, prelim PMID 6697483, review PMID 33906696, consistent with changes in hypothalamic purine balance driving endocrine changes. IMG

PCOS is a fairly common disorder in the general population (6-12%), but is more than 4x more common among patients with BPD: PMID 20149393, review PMID 28891300. IMG

Increased suicidal ideation is correlated with acne, often considered, especially in PCOS, as an excess of testosterone, PMID 9892952. This effect may be indicative of underlying pathophysiology, rather than the patient's vanity.

https://www.sciencedirect.com/science/article/abs/pii/S0006322323000057?via%3Dihub 

PMID 1547678

PCOS is a fairly common disorder in the general population (6-12%), but is more than 4x more common among patients with BPD: PMID 20149393, review PMID 28891300. This is consistent with hypothesized mechanism of BPD (shunting purines from Io to i to x, resulting in excess x), and suggests that treatments that block Io to i conversion (e.g. duloxetine, quetiapine, loxapine, chlorpromazine, fluphenazine, etc. as well as ACEi/ARBs) may help treat PCOS. ACEi lisinopril effectively reduced the metabolic and endocrine distortion (obesity, ovarian hypertrophy, elevated testosterone) of PCOS in animal model PMID 34756399 and may already be indicated based on risk of HTN related to PCOS-induced metabolic syndrome PMID 21565677. Allopurinol or febuxostat may also be helpful, based on proposed mechanism. Inositol is an OTC with limited evidence for treating PCOS PMID 28642705 Cochrane PMID 30570133, which may provide benefit in other BPD symptomatology. IMG

Metabolic syndrome in the context of pregnancy has been studied separately than metabolic syndrome outside of pregnancy, but share the uric acid connection: higher uric acid levels correlate with worse metabolic syndrome (e.g. preeclampsia PMID 32338457, 26260220, gestational diabetes PMID 19788971) consistent with significant role of xanthine in metabolic syndrome.

Preeclampsia risk of seizures may be mitigated with hydralazine, an adenine-analogue PMID 2441099.

Doxycycline is a tetracycline antibiotic that seems likely to be a hypoxanthine analogue. Doxycycline decreases testosterone production PMID 6683057, suggesting that hypoxanthine may have a similar effect. Allopurinol also shows suppression of testosterone, apparently via LH in gout-treated men PMID 6442150. Testosterone is constantly elevated in PCOS, suggesting the possibility of a hypoxanthine deficit.  IMG

Other compounds noted to have similar anti-testosterone effects are primarily those that have already been identified here as hypoxanthine similar: PMID 1615704

Adaptation to higher altitude, which may activate the same purine pathway, decrease testosterone concentrations PMID 23524530. The inability to decrease testosterone (via increased hypoxanthine?) increases risk of chronic mountain sickness.

Different than metabolic syndrome, often treated with guanine-analogue metformin, uric acid levels in PCOS patients did not respond to metformin, but did respond to estrogen + anti-testosterone (hypoxanthine/xanthine-similar) cyproterone PMID 18375410. Of note, several performance-enhancing drugs are guanine-similar (e.g. piperine, meldonium) while others are L-DOPA similar (trimetazidine, meldonium) consistent with guanine as a pro-testosterone. Metformin decreases testosterone in men at 1 mo PMID 33536253 and 3 mo PMID 35002984, suggesting that PNP inhibition is greater than the pro-testosterone guanine signaling in men. Testosterone is also decreased in PCOS patients taking metformin PMID 12724019. Metformin addresses ammenorhea and changes sex-hormone levels in women with metabolic syndrome associated with antipsychotic 22711171.

Of note, ondansetron increases testosterone in mice PMID 15587814, consistent with proposed mechanism of GMP-reductase inhibitor and treatment for dystonia. Muscle wasting in hypercortisolism may be due to increase in I-derivatives at the expense of G-derivatives, reducing testosterone signal.

Statins, consistent with proposed mechanism of PNP inhibition, are known to decrease testosterone levels meta-analysis PMID 23448151

Valproate decreases testosterone 29513282 sys rev 29940375, as does SAH: SAM-e increases testosterone in rats 3029509: in mice, testosterone increases renal, not hepatic, SAM-e but not SAH, modifying epigenetics 1581345. These data are consistent with valproate's action as an MAT inhibitor. Testosterone is closely related to substantia nigra "dopaminergic"/ guanine-sensitive neurons 24618531

Fluphenazine is noted to have effects on reproduction in animals treated with LAI formulation: 26491959

Acetazolamide therapy of menstrual-related fluctuations in Parkinson's disease 8474504

24271059 review of purinergic signaling