Abnormal Uterine Bleeding- O

What is ovulatory dysfunction?

Describes a patient who

• Is not ovulating (anovulation)

• Has infrequent or irregular ovulation (oligoovulation)

What is Adolescent HPO Immaturity?

Cycles vary during first few years after menarche due to irregularities in ovulation

True or false, The older you are when menarche hits, the longer it takes for your cycle to regulate

True. Duration of time it takes to establish regular ovulatory cycles increases with increasing age at time of menarche

If a patient hits menarche at <12 years old, when can they expect their cycle to be ovulatory?

1 year

If a patient hits menarche between 12 and 13 years old, when can they expect their cycle to be ovulatory?

3 years

If a patient hits menarche at >13 years old, when can they expect their cycle to be ovulatory?

4.5 years

In Adolescent HPO Immaturity, what causes estrogen to be sustained in absence of progesterone?

No midcycle LH surge

In Adolescent HPO Immaturity, estrogen secretion being sustained in absence of progesterone leads to what?

Proliferation of the endometrium beyond ability of estrogen to maintain it

In Adolescent HPO Immaturity, what is the result of the uncontrolled proliferation of the endometrium?

Irregular, heavy bleeding occurs when the endometrium becomes unstable and continues until estrogen-induced repair takes place

What is the most common cause of abnormal uterine bleeding in adolescents?

Adolescent HPO Immaturity

What are signs and symptoms of Adolescent HPO Immaturity?

Heavy menstrual bleeding

What are treatment options for Adolescent HPO Immaturity?

The underlying cause of abnormal uterine bleeding determines treatment

• Time and observation

• NSAIDS

• Hormonal contraception

What is Polycystic Ovarian Syndrome (PCOS)?

Endocrine disorder that can cause androgen excess, hirsutism, and infertility

When does PCOS typically begin?

Soon after menarche

True or false, insulin resistance can be an etiology of PCOS?

True.

What is insulin resistance?

Insulin resistance causes cells to become less sensitive to insulin —> the body increases insulin (hyperinsulinemia) to maintain normal blood glucose levels

What are risk factors for insulin resistance?

Genetics, obesity, physical inactivity, diet, inflammation, hormonal imbalances, aging, sleep deprivation, gut microbiota, medications

A patient with PCOS that develops insulin resistance is at risk for which condition?

Diabetes Mellitus

What are signs and symptoms of PCOS?

Menstrual disorder- oligomenorrhea, amenorrhea,

Insulin resistance and associated conditions- metabolic syndrome, nonalcoholic fatty liver disease, Obstructive sleep apnea

Dysmenorrhea

Cysts

Fertility Issues

Extreme fatigue during day/ insomnia at night/ never feeling rested

Skin disorder r/t androgen excess: acne, hirsutism, alopecia

Weight gain- abdominal bloating, “PCOS belly”

Pregnancy complications

What are some risk factors for PCOS?

Oligoovulatory infertility

Obesity

DM - type 1, typ2, and gestational

History of premature menarche

First degree relative with PCOS

Ethnicity: Mexican American, Australian aborigines

Drugs: valproate

What other conditions should be ruled out when completing a diagnosis of exclusion for PCOS?

Rule out pregnancy, thyroid disorder, prolactinoma, pituitary or hypothalamic suppression, and medication-induced infrequent menses

How is PCOS diagnosed?

2 of 3 features required for diagnosis": Rotterdam Criteria

1. Oligo-ovulation or anovulation manifested by irregular menstrual cycles (oligomenorrhea or amenorrhea 3+ months without menses)

2. Biochemical or clinical evidence of hyperandrogenism (hirsutism, alopecia, acne)

3. Polycystic ovaries on Ultrasound- at least 1 ovary must have >20 follicles/ovary and/ or ovarian volume > 10 mL in either ovary - PCOM (polycystic ovary morphology)

Why is diagnosing PCOS in adolescents challenging?

Many symptoms of PCOS mimic normal physiologic responses of puberty

When is it suitable for adolescents to be evaluated for PCOS?

At least 18 months following menarche and should not be diagnosed with PCOS unless they meet all 3 Rotterdam criteria

What does Phenotype A of PCOS consist of?

This is “full PCOS” or “classic PCOS”= biochemical or clinical hyperandrogenism + oligoovulation+ PCOM

What does Phenotype B of PCOS consist of?

This is “classic PCOS” = hyperandrogenism + oligoanovulation, NO PCOM

What does Phenotype C of PCOS consist of?

This is “ovulatory PCOS” = hyperandrogenism + PCOM, no oligoanovulation

What doe Phenotype D of PCOS consist of?

This is “non-hyperandrogenic PCOS” = includes oligoanovulation + PCOM , no hyperandrogenism

What PCOS phenotype(s) constitutes 2/3rds of total number of people with PCOS?

Phenotype A and B

What are some consequences of PCOS?

Infertility, endometrial cancer, ovarian cancer, DM, Hypertension, and CVD

What assessments should be completed when evaluating for PCOS?

Blood pressure

BMI: 25-29 overweight, >30 obese

Waist circumfrence, to determine body fat distribution

• > 35 inches increased risk of developing obesity related conditions

Presence of stigmata of hyperandrogenism and insulin resistance

• Acne, hirsutism, androgenic alopecia, acanthosis nigricans

Pelvic exam: ovarian enlargement

True or false, There needs to be 2 polycystic ovaries on ultrasound to confirm PCOS diagnosis.

False. Presence of 1 polycystic ovary is sufficient to provide diagnosis.

What labs should be drawn to rule out other causes of PCOS symptoms?

B-hCG

Prolactin

TSH

17-OHP- to rule out congenital adrenal hyperplasia

FSH and Estradiol

What should be drawn to establish hyperandrogenemia?

Total testosterone + Sex Hormone - Binding Globulin (SHBG)

DHEA-S - to rule out androgen-secreting adrenal tumor

What should be drawn to evaluate for metabolic abnormalities?

Fasting lipid profile

2-hour oral GTT

What is problematic about congenital adrenal hyperplasia?

Patient lacks enzymes involved in cortisol and aldosterone synthesis - enzyme 21 hydroxylase or 11 hydroxylase

No 21 hydroxylase means no/low cortisol

What are signs and symptoms of congenital adrenal hyperplasia?

“Typical appearing” genitals at birth

Early appearance of pubic hair and other signs of early puberty

Severe acne

Rapid growth during childhood

Irregular menstrual periods

Infertility

Androgen excess

What is the purpose of a Serum Total Testosterone?

Measured in suspected PCOS or with clinical signs of androgen excess

• Mild increase in testosterone levels —> consistent with PCOS

• >200 ng/dL —> ovarian tumor —> Pelvic Ultrasound

What is Sex hormone-binding globulin (SHBG)?

A glycoprotein synthesized in the liver that binds to androgens and estrogens

Decreased SHBG levels = decreased binding of testosterone = increased unbound testosterone in the body = androgen related expressions available in the body (hirsutism, acne, etc)

SHBG is increased in which conditions?

Hyperthyroidism

Hepatic cirrhosis

HIV

Pregnancy

Increased age

Marked weight loss

SHBG is decreased in which conditions?

Hirsutism

Acne

PCOS

Hypothyroidism

Acromegaly

Obesity

What is DHEA-S?

A weak androgenic steroid hormone produced in the adrenal gland

What does a Serum DHEA-S tell us?

May solidify a diagnosis of PCOS or raise concern about androgen-secreting adrenal tumor

What trend in value for a Serum DHEA-S indicates PCOS?

Levels in high- normal range or mildly above

What does this image depict?

Adrenocortical carcinoma

What trend in value for a Serum DHEA-S indicates Addison Disease, adrenal hypoplasia?

Decreased levels of DHEA-S

What trend in value for a Serum DHEA-S indicates Adrenal Carcinoma?

Very high increase (above 700 ug/dL)

What is hirsutism?

Presence of excessive terminal (coarse) hair in androgen-sensitive areas- upper lip, chin, chest, back, abdomen, arms, and thighs

What is virilization?

More excessive than hirsutism w/ additional evidence of masculinization

• Ambiguous external genitalia

• Increased muscle mass

• Acne

• Balding

• Deepening of voice

• Breast/Chest atrophy

• Amenorrhea/ oligomenorrhea

• Increased libido

What are some drugs that decrease DHEA-S?

Insulin

COC

Corticosteroids

CNS agents

What are some drugs that Increase DHEA-S?

Metformin (why it is given sometimes in PCOS)

Prolactin

Danazol

What are some overall goals for treatment of PCOS?

Achieve regular menstrual pattern

Prevent endometrial hyperplasia and endometrial cancer

Decrease infertility (if pregnancy is desired)

Decrease hirsutism and acne

Decrease associated complications: type II diabetes, CVD

How do combination hormonal contraceptives help to regulate the cycle?

Low dose CHC’s:

• Suppress LH secretion

• Suppress ovarian androgen secretion

• Increase circulating SHBG

What method is most commonly used for long term management of regulating cycles in PCOS patients?

Low dose CHCs

True or false, We are concerned about increased risk of endometrial hyperplasia and cancer in every patient with irregular menses.

False, if menstrual bleed occurs at least every 3 months they are having endometrium shedding often enough to prevent increased risk of endometrial hyperplasia or endometrial cancer

What is an alternative for endometrial protection and regulating cycles?

Progestin Only Contraceptives.

• caveat: associated with abnormal bleeding patterns in many users

What are the progesterone options for regulating cycles?

1. Periodic provera (medroxyprogesterone acetate [MPA] to obtain withdrawal bleed- every 3 months)

2. Provera, 5-10 mg PO everyday for 12 days

3. Prometrium 200 mg PO every night at bed time for 12 days

4. LNG-IUS

What are treatment options for infertility?

Smoking and alcohol cessation

Weight loss

Assisted reproductive therapy : Clomiphene citrate or letrozole (esp. in PCOS with BMI >30), gonadotropins

Surgery : ovarian drilling, laparoscopic procedure, laser

True or false, Letrozole can be used long term.

False, Letrozole cannot be used long term

What is the purpose of Letrozole?

increase live birth rates in people with PCOS and obesity

What are some side effects of Letrozole?

Hot flashes

Fatigue

Dizziness

What are treatment options for Hirsutism?

COCs

Spironolactone 25-100 mg twice a day

What are some things to consider when prescribing Spironolactone?

Full clinical effect may take 6 months

It is a K-sparing diuretic - can cause or exacerbate hyperkalemia : use w/ caution in renal impairment

Use spironolactone with good contraception: can interfere with development of external genitalia in male fetus

Some may experience changes in menstrual patterns

What if Vaniqa?

Treatment for facial hirsutism. Apply thin layer twice a day at least 8 hours apart to affected area. rub cream into skin thoroughly, do not wash area for 4 hours

What is the dosage recommendation fo Metformin in PCOS patients?

1,500-2,000mg/ day in divided doses

True or false, ovulation will increase with Metformin treatment.

True. Ovulation rates will likely improve with treatment so it is important to discuss contraceptive options

What is the recommended starting dose for Metformin?

500 mg ER form PO with a meal

What is the indication for start of Metformin in PCOS patients?

Reserved for people with PCOS and with impaired glucose tolerance, increased fasting insulin levels, and acanthosis nigricans

What is Ovasitol (myo-inositol)?

A powder supplement designed to promote healthy hormone levels to support regular menstrual cycles, ovarian health, and fertility. Not FDA approved

People with PCOS found it to be significantly superior in placebo in improving ovulatory frequency and weight loss

What is Berberine?

Nature’s metformin. Decreases serum cholesterol by:

• Decreasing intestinal cholesterol abs

• Increasing fecal cholesterol excretion

• Inhibits proprotein convertase subtilisin kexin 9 (PCSK9)

• Upregulates LDL Receceptors

What is the benefit of spearmint herbal tea?

Spearmint herbal tea has significant anti-androgen effects in polycystic ovarian syndrome

What are natural remedies for PCOS treatment?

Spearmint herbal tea, castor oil packs, heating pad, OTC Progesterone cream??

True or false, Hypothyroidism is common in people of childbearing age.

True

What is the relationship between the thyroid and pregnancy?

Can impact ability to get pregnant

Can impact a pregnancy

Can impact postpartum period

What is hypothyroidism?

Insufficient thyroid hormone production or ingestion

What is the most common cause of primary hypothyroidism?

Autoimmune Thyroiditis (Hashimoto’s)

What are common symptoms of hypothyroidism?

Fatigue

Lethargy

Cold Intolerance

Dry skin

hair loss

Constipation

What are common gynecologic-related symptoms of hypothyroidism?

Precocious or delayed puberty

Menstrual disorder

Infertility due to anovulation

What are some physical exam findings associated with hypothyroidism?

Diffuse, firm goiter with a rough contour

• some glands normal in size and consistency

• pain and tenderness of thyroid gland = not usual

Classic signs and symptoms present in 1/3 of patients

Why can it be difficult to confirm whether some signs and symptoms are indicative of hypothyroidism?

Because some typical symptoms can be difficult to distinguish from those associated with normal pregnancy, menopause, aging, and life stress

What other lab is typically always drawn with Serum TSH?

Prolactin, because hypothyroidism can increase prolactin.

What is the next step if a patient’s TSH is increased?

Draw/reflex unbound/ free thyroxine (T4) to confirm hypothyroidism

What trend in labs indicates possible hypothyroidism?

Increased TSH.

Normal range: 0.5-6.3 uIU/mL, depending on age and sex

What is treatment for hypothyroidism?

Levothyroxine; generally started at lower end of anticipated requirement

What factors are considered when prescribing Levothyroxine?

Patient’s body weight and severity of hypothyroidism

What causes hyperprolactinemia?

Anterior pituitary secretes prolactin —> excess prolactin inhibits secretion of GnRH —> production of FSH and LH is affected

What are causes of hyperprolactinemia?

Hypothyroidism; most common cause

Prolactin-secreting pituitary adenomas or other pituitary or hypothalamic tumors

• tumors disrupt delivery of dopamine

Breast/chest wall surgery, cervical spine lesions, or herpes zoster

Renal insufficiency and macroprolactinemia due to decreased clearance

What is the relationship between hypothyroidism and hyperprolactinemia?

Decreased levels of T4 —> increased levels of thyrotropin releasing hormone —> increased prolactin secretion

Prolactin suppresses GnRH secretion —> low gonadotropin and estradiol—> amenorrhea

What is a common cause of secondary amenorrhea?

Hyperprolactinemia

Prolactin suppresses which process?

GnRH secretion. This results in low gonadotropin and estradiol and leads to amenorrhea

What are medications that increase prolactin levels?

Drugs that decrease dopamine levels or inhibit dopamine action—> Increase Prolactin

Amphetamines

Benzodiazepines

Butyrophenones

Metoclopramide

Methyldopa

Opiates

Phenothiazines

Reserpine

Tricyclic Antidepressants

What are some nonpharmacological interventions used to treat hyperprolactinemia?

Lactogenic herbs: Fenugreek seeds, Moringa, Galega, Shatarvari

Lactogenic foods:

Vegetables: fennel root, beetroot, carrots, yam, sweet potato, dark leafy greens

Fruit: dates, figs, apricots, papaya

Some fats: butter, olive oil, coconut oil, sesame oil

Grains: barely, oats and oatmeal, quinoa, rice, brewer’s yeast

Nuts and seeds: almonds, sesame seeds, sunflower seeds, chia seeds, hemp seeds

Legumes: chickpeas, lentils, peas

Seasonings: majoram, basil pepper, fennel

What are signs and symptoms of hyperprolactinemia

Abnormal menstrual cycles- amenorrhea

Anovulation and amenorrhea

Infertility d/t anovulation

Galactorrhea

Decreased libido

Bone loss

Vaginal dryness

How many people with hyperprolactinemia will experience galactorrhea?

1/3 of people with hyperprolactinemia

How is hyperprolactinemia diagnosed?

Prolactin draw
Normal range (<50 years; premenopausal): 3.34-26.72 ug/L

>50 years (postmenopausal): 2.74-19.64 ug/L

<15-20 ng/mL excludes hyperprolactinemia

Mildly increased levels (<50 ng/dL)- confirm with repeat test and med stim review —>

Increased levels (>100 ng/mL)

• MRI to rule out pituitary tumor

What should you do if you repeat a Serum Prolactin in a patient that previously had an elevated (<50 mg/mL), and it comes back normal?

Nothing, no treatment is required

What are treatment options for hyperprolactinemia?

Treat thyroid disorder if present

Dopamine agonist restores ovulatory function and menses within several weeks

Bromocriptine (Parlodel)

• Short half life —> administered every day at bed time or twice a day

Cabergoline (Dostinex)

• Administer twice a week

• Fewer side effects that bromocriptine

• Increased potency and duration of action

What typically happens to amenorrhea and galactorrhea after a patient discontinues treatment for hyperprolactinemia?

These symptoms often recur within weeks and most people require long-term treatment

What treatments can be used in hyperprolactinemia if contraceptives are NOT needed?

Cyclic progestin - prevents chronic unopposed estrogen exposure

Combined estrogen/progestin - prevent consequences of chronic estrogen deficiency

Estrogen, 0.625mg with Provera 2.5 mg every day

What treatments can be used in hyperprolactinemia if contraceptives ARE needed?

Low dose COC