PMOS (PCOS) & Endometriosis

A new name that reflects the disease. "PMOS used to be called polycystic ovary syndrome (PCOS)." "Polyendocrine metabolic ovarian syndrome (PMOS) is a hormone condition that can affect hair growth, periods, fertility and mood. There is no cure, but treatments and lifestyle changes can help." It is "the most common endocrine pathology in females of reproductive age worldwide," and "recent literature increasingly recognizes it as a metabolic disease." Genes matter a great deal — "Twin studies have estimated that about 70% of PMOS pathogenesis is attributable to genetic components" — and "Your risk of PCOS may be higher if you have obesity or if you have a mother, sister, or aunt with PCOS."

Androgens stop ovulation. The OWH: "In women with PCOS, the hormonal imbalance interferes with the growth and release of eggs from the ovaries (ovulation)." In the ovary, "LH stimulates ovarian androgen production, while the relative decrease in FSH prevents adequate stimulation of aromatase activity in granulosa cells, thereby decreasing the conversion of androgens to the potent estrogen estradiol."

Insulin resistance feeds the androgens — and the loop is hard to break. Insulin normally moves glucose into cells; when cells resist it, the body makes more insulin. "To balance out the high levels of insulin, the body makes more androgens" and "It is difficult to disrupt this cycle, which is why treating PCOS can be challenging." StatPearls calls it "The bidirectional link between hyperinsulinemia and androgen excess" and adds that "Insulin resistance in PMOS is independent of adiposity." So a normal weight does not rule it out.

The endometrium sees estrogen without a break. "Elevated serum androgens are converted peripherally to estrogens, mostly estrone. As conversion occurs primarily in the stromal cells of adipose tissue, estrogen production is augmented in obese PMOS patients." Without ovulation there is no progesterone to balance it: "Unopposed estrogen stimulation of the endometrium may lead to endometrial hyperplasia." The OWH ties it together — "Problems with ovulation, obesity, insulin resistance, and diabetes (all common in women with PCOS) increase the risk of developing cancer of the endometrium (lining of the uterus or womb)." There is also "low-grade chronic inflammation," with C-reactive protein raised "irrespective of obesity."

The symptoms start at puberty and are easy to dismiss. "Symptoms of polyendocrine metabolic ovarian syndrome (PMOS) usually start in girls and young women under the age of 18, at puberty, and continue until menopause." The NHS list: "irregular periods or long gaps between your periods," "excessive hair growth (hirsutism) or hair loss," "weight gain or difficulty losing weight," "difficulty getting pregnant," "mental health problems, such as depression or anxiety," "oily skin and acne," "feeling very tired," and "thick, dark patches of skin on the neck or armpits." OWH adds that women "may miss periods or have fewer periods (fewer than eight in a year)." Many people never mention them: "As a result, many women aren't diagnosed with PCOS until they have trouble getting pregnant, or until they have menstrual irregularities."

Two of three, after ruling out mimics. The 2023 international guideline, relayed by StatPearls, says the diagnosis in an adult "requires the presence of 2 out of the following 3 criteria, as well as the exclusion of differential diagnoses with similar clinical features": clinical or biochemical hyperandrogenism, ovulatory dysfunction, and polycystic ovaries on ultrasound or a raised AMH. "PMOS is a diagnosis of exclusion" — the mimics include "thyroid disease, hyperprolactinemia, and atypical congenital adrenal hyperplasia due to 21-hydroxylase deficiency." An ultrasound is not always needed: "When irregular menstrual cycles and hyperandrogenism are present, neither ultrasound nor AMH testing is necessary for the diagnosis of PMOS in adults." In adolescents "both hyperandrogenism and ovulatory dysfunction must be present," and ultrasound and AMH "are not recommended in this population due to their low specificity." Weight does not decide it — "a normal BMI should not exclude a diagnosis of PMOS."

Virilization points elsewhere. "Signs of virilization, eg, increased muscle mass, reduced breast size, deepening of the voice, and clitoromegaly, are not commonly seen in PMOS." "In such cases, clinicians should be more concerned about the possibility of an androgen-producing tumor in either the ovary or the adrenal gland." Likewise, "Acute onset or fast progression of hyperandrogenism in adulthood should prompt consideration of adrenal or ovarian tumors." A deepening voice or rapidly worsening hair growth is reported, not charted as "PMOS."

The metabolic load. "More than one-half of women with PCOS have insulin resistance." "Patches of thickened, dark, velvety skin, called acanthosis nigricans, are associated with insulin resistance." "About 25% to 45% of women with PCOS have metabolic syndrome." "More than one-half of women with PCOS will have either type 2 diabetes or prediabetes before their early 40s." Add high blood pressure, "higher levels of LDL (bad) cholesterol and low levels of HDL (good) cholesterol," "3 times the increased risk of MASLD," and sleep apnea — "Women with PCOS are at much higher risk for obstructive sleep apnea than others, including those without PCOS and those with obesity." A nuance worth knowing: a 32-year study of women aged 72 to 91 "showed no evidence of an increase in all-cause mortality or cardiovascular death." And it does not stop at menopause — "their PCOS hormonal imbalance does not change with age, so they may continue to have symptoms of PCOS."

Mood and eating. "Depression and anxiety are common among women with PCOS." "Major depression, recurrent depression, and suicide attempts were also higher in PMOS women. Screening and identifying depression and anxiety disorders should be conducted, and appropriate treatment should also be given." And because so much care focuses on weight: "Eating disorders and disordered eating should be considered in PMOS, regardless of weight, especially in the context of weight management and lifestyle interventions."

Fertility — common, and treatable. "Having PCOS does not mean you can't get pregnant. PCOS is one of the most common, but treatable, causes of infertility in women." The reason is anovulation: "If you don't ovulate, you can't get pregnant." "Fertility is likely to return with a modest weight loss of about 5%." When medicine is needed, the same guideline (via StatPearls) says "The first-line therapy for infertility in PMOS patients is letrozole"; clomiphene and laparoscopic ovarian drilling are other options. Pregnancy carries higher rates of miscarriage, gestational diabetes, preeclampsia and cesarean birth, and "Your baby also has a higher risk of being heavy (macrosomia) and of spending more time in a neonatal intensive care unit (NICU)." Before pregnancy: "Reaching a healthy weight before you get pregnant." and "Taking folic acid. Talk to your doctor about how much folic acid you need."

What it is. "Endometriosis is where cells similar to those in the lining of the womb (uterus) grow in other parts of the body." "Endometriosis is an estrogen-dependent inflammatory disease." "The main clinical manifestations of the disease are chronic pelvic pain and impaired fertility." The growths are "benign (not cancerous). But they can still cause problems." It "affects an estimated 10% of reproductive-aged females worldwide," rising to "up to 35% to 50%, among patients with chronic pelvic pain or infertility."

Why it hurts. "Endometriosis growths may swell and bleed in the same way the lining inside of your uterus does every month — during your menstrual period. This can cause swelling and pain because the tissue grows and bleeds in an area where it cannot easily get out of your body." Trapped blood and inflammation leave damage: "Trapped blood in the ovaries can form cysts," and scar tissue and adhesions — "type of tissue that can bind your organs together" — "may cause pelvic pain and make it hard for you to get pregnant." Estrogen is the fuel: "These ectopic implants are driven by estradiol, which promotes cellular proliferation, adhesion, fibrosis, inflammation, immune dysfunction, and the development of neovascularization and neurogenesis."

How it gets there. "The most widely accepted theory is retrograde menstruation, in which viable endometrial cells reflux through the fallopian tubes and implant within the peritoneal cavity; however, as this occurs in many individuals without disease, additional factors are necessary for lesion development." Tissue can also be moved during surgery such as a cesarean or hysterectomy. The ovaries are the most common site, and "Sometimes, endometriosis is found in areas outside the pelvis, such as in the chest." Risk is higher with "early menarche (before age 10), short menstrual cycles, heavy or prolonged bleeding, low body mass index (BMI), nulliparity, and a first-degree family history."

The symptoms. The NHS list: "severe period pain" "that stops you from doing your normal activities"; heavy periods "where you need to change your pads or tampons every 1 to 2 hours"; "pain in your lower tummy and back (pelvic area)"; "pain when you poo or pee"; "pain during or after sex"; "extreme tiredness (fatigue)"; and "pain or bleeding in other areas, such as in the chest, which may cause shortness of breath and coughing up blood." "You may also have difficulty getting pregnant and have low mood or anxiety." StatPearls: "The hallmark symptoms are chronic, cyclic pelvic pain, dysmenorrhea, dyspareunia, dyschezia, dysuria, and infertility, though symptom severity does not correlate with disease extent." So a small amount of disease can hurt a lot, and a lot can hurt little.

Diagnosis is slow — which is why pain should not be normalized. "Diagnosis is frequently delayed, often taking several years from initial symptom onset, with many patients consulting multiple clinicians before the condition is identified and confirmed." Education "encourages timely consultation with a clinician rather than normalizing debilitating menstrual pain." In the NHS pathway, the GP does a physical examination, including an internal exam, and blood tests; further tests include an ultrasound — "this may be done on your tummy or inside your vagina" — an MRI scan, and a laparoscopy, where "this can confirm if you have endometriosis." Pregnancy is excluded first — "ectopic pregnancy and early pregnancy complications must also be excluded."

What confirms it. "Histopathologic evaluation remains the gold standard for confirming the diagnosis of endometriosis." The OWH puts it plainly — "Surgery is the only way to be sure you have endometriosis." — and describes a trial of hormones: "If your pain gets better with hormonal medicine, you probably have endometriosis. But, these medicines work only as long as you take them. Once you stop taking them, your pain may come back."

Combined hormonal contraception is the workhorse. For PMOS, the 2023 international guideline, via StatPearls: "The first-line treatment for women with symptomatic PMOS, specifically for issues such as menstrual irregularities, hirsutism, and acne, is a combined hormonal contraceptive." It works because "The progestin component of these contraceptives helps to lower LH levels, which in turn reduces ovarian androgen production and increases levels of sex hormone-binding globulin." It also lowers the risk of endometrial cancer. For endometriosis, "First-line treatments, including nonsteroidal anti-inflammatory drugs, combined hormonal contraceptives, and progestins, eg, dienogest, remain foundational for symptom control," and "If you are not trying to get pregnant, hormonal birth control is generally the first step in treatment." But "Hormonal treatment works only as long as it is taken," and "You will not be given hormones if you're trying to get pregnant." Before starting, "Identifying any contraindications to hormonal contraceptives in all patients being considered for this therapy is critical."

The combined pill’s boxed warning and clot signs (Yaz label). "Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke." The patient information lists what needs a call right away: "Persistent leg pain," "Sudden shortness of breath," "Sudden blindness, partial or complete," "Severe pain in your chest," "Sudden, severe headache unlike your usual headaches," "Weakness or numbness in an arm or leg, or trouble speaking," and "Yellowing of the skin or eyeballs." Drospirenone also holds on to potassium: "DRSP has anti-mineralocorticoid activity. Do not use in patients predisposed to hyperkalemia." And around surgery: "Stop at least 4 weeks before and through 2 weeks after major surgery."

Second-line for endometriosis: shutting estrogen down. GnRH agonists and antagonists "induce a hypoestrogenic state and are effective for pain, but are less favored due to notable adverse-effect profiles and do not improve fertility." They cause "vasomotor symptoms, vaginal dryness, sleep disturbance, mood changes, and accelerated bone loss," "often requiring add-back therapy with estrogen or progesterone." The OWH: "This treatment causes a temporary menopause." Elagolix (Orilissa) label: it "causes a dose-dependent decrease in bone mineral density (BMD). BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment," so "Limit the duration of use because of bone loss." It is contraindicated in pregnancy and in known osteoporosis. "Advise women to use effective non-hormonal contraceptives during treatment with ORILISSA and for 28 days after discontinuing ORILISSA" — lighter bleeding "may reduce the ability to recognize the occurrence of a pregnancy in a timely manner." And mood: "Suicidal ideation and behavior, including one completed suicide, occurred in subjects treated with ORILISSA in the endometriosis clinical trials."

The PMOS off-label drugs. Metformin "may help some women with PCOS symptoms. It is not approved by the FDA to treat PCOS symptoms." Anti-androgens "are not approved by the Food and Drug Administration (FDA) to treat PCOS symptoms. These medicines can also cause problems during pregnancy," so they are paired with contraception because they "are highly teratogenic." GLP-1 receptor agonists produce more weight loss than metformin, but "GLP-1 has not yet been approved for PMOS management as an indication."