#56 – Polycystic Ovarian Syndrome



***LISTEN TO THE PODCAST HERE***



Background

  • First described by Stein and Leventhal in 1935
  • The most common cause of infertility in women
    • Up to 30% of women seeking infertility treatment
  • Affects 6-12% of US women ( or 1 in 10)  of reproductive age
  • Increases life-time risk of developing:
    • Obesity
    • DMII
    • Cardiovascular disease
    • Breast and endometrial cancers

Pathophysiology

  • Two-Hit Hypothesis
    • First – genetic predisposition
      • Heritable traits and gene variations affecting ovarian function, insulin resistance, obesity, and DMII
        • 25% of patients with PCOS have a mother with PCOS
      • Congenital virilization
        • Congenital adrenal hyperplasia
      • Disturbed fetal nutrition
    • Second – provocative trigger
      • Insulin-resistant hyperinsulinemia
      • Puberty
  • This then leads to the classic pathology of:
    • Functional ovarian hyperandrogenism
    • Hyperinsulinism and obesity
    • Luteinizing hormone (LH) excess
Up-to-Date

Definition and Diagnostic Criteria

  • Adults
    • Rotterdam Criteria
      • 2 of 3 following criteria:
        • Anovulation
        • Hyperandrogenism
        • Polycystic ovaries
Up-to-Date
  • Adolescents
    • Developed in 2015 and consist of otherwise unexplained persistent hyperandrogenic oligo-anovulatory menstrual abnormality based on age and stage appropriate standards
Up-to-Date

Clinical Features

  • Cutaneous Hyperandrogenism
    • Hirsutism
      • Graded by Ferriman-Gallwey scoring system, which quantitates the extent of hair growth in androgen sensitive areas
        • Hirsutism is defined as a score ≥ 8
    • Acne
      • Moderate comedonal acne or severe inflammatory acne suggests hyperandrogenemia
  • Ovarian Findings
    • Menstrual
      • Primary Amenorrhea
        • Lack of menarch by 15 years of age or > 3 years after onset of breast development
      • Secondary Amenorrhea
        • > 90 days without a menstrual cycle after previously menstruating
      • Oligomenorrhea
        • During the first five years after menarache:
          • Year 1 – < 4 cycles in the year
          • Year 2 – < 6 cycles in the year
          • Year 3-5 – < 8 cycles in the year
            • Missing ≥ 4 cycles in the year
          • Year 6+ – < 9 cycles in the year
            • Missing ≥ 3 ycles in the year
      • Excessive uterine bleeding
        • More frequently than every 21 days or excessive bleeding
          • PCOS is the most common cause of excessive uterine bleeding in adolescents
    • Polycystic ovaries
  • Obesity
    • Chief complaint in up to 20% of PCOS patients
  • Sleep apnea or
  • Nonalcoholic fatty liver
  • Manifestations of insulin resistance
    • Acanthosis nigricans
    • Metabolic syndrome
      • Up to 25% of PCOS patient

Diagnostic Work-Up

  • Need to be performed at a lab with highly sensitive assay capability
  • If using hormonal OCP, need to be stopped 2-3 months before testing
    • Due to suppression of testosterone
  • Testosterone (1st step)
    • Should be early morning as testosterone levels fall by the afternoon
    • Serum total testosterone
      • Normal – 40-60 ng/dL
      • > 150 ng/dL is diagnostic
    • Serum free testosterone
      • More sensitive than total, but are less standardized
      • Only reliable if calculated from the total testosterone
  • Endocrine Screening Panel (2nd step if elevated testosterone)
    • Beta-hCG
    • FSH/LH
      • Slightly elevated LH with a slightly decreased FSH is characteristic of PCOS
      • Markedly elevated FSH = primary hypogonadism
      • Markedly decreased LH = secondary hypogonadism
    • TSH
  • Screening for Common non-PCOS causes of hyperandrogenism (3rd step if endocrine screening is normal)
    • 17-hydroxyprogesterone (17OHP)
      • Drawn at 0800 and with the patient either amenorrheic or within the fist 10 days after the start of her menstrual cycle
      • > 170 ng/dL suggests CAH
    • DHEAS
      • > 700 mcg/dL suggests adrenal tumor
    • Prolactin
      • Hyperprolactinemia can causes gonadotropin deficiency
      • > 25 ng/m: suggests prolactinoma
    • Serum cortisol
      • < 10 mcg/dL rules out Cushing syndrome
    • Insulin-like grown factor (IGF-1)
      • Rule out acromegaly
  • Other tests
    • Chronic disease panel
      • CBC, ESR/CRP, CMP
    • Lipid Panel (for adults)
      • LDL, HDL, triglycerides
  • Transvaginal ultrasound of ovaries
    • Increased overall size
    • Increased number of distinct follicles
      • ≥ 6 is diagnostic

Treatment

  • Adolescents
    • Antiandrogen
      • Estrogen-progestin combination OCPs
        • Can also use GnRH agonist (leuprolide)
      • Targeted antiandrogen therapy (if no improvement after 6 months)
        • Spironolactone
        • Finasteride
    • Insulin resistance
      • Biguanide (metformin)
      • Thiazolidinediones (pioglitazone, rosiglitazone)
  • Adults
    • Same as above, but add:
      • Dyslipidemia therapy

The Cottage Physician (1893)



References

  1. Stein IF, Leventhal ML.  Amenorrhea associated with bilateral polycystic ovaries.  AJOG. 1935;29(2):181-191 [article]
  2. Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. The Journal of clinical endocrinology and metabolism. 2004; 89(6):2745-9. [pubmed]
  3. Franks S, Stark J, Hardy K. Follicle dynamics and anovulation in polycystic ovary syndrome. Human reproduction update. ; 14(4):367-78. [pubmed]
  4. Barthelmess EK, Naz RK. Polycystic ovary syndrome: current status and future perspective. Frontiers in bioscience (Elite edition). 2014; 6:104-19. [pubmed]
  5. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertility and sterility. 2004; 81(1):19-25. [pubmed]
  6. Azziz R, Carmina E, Dewailly D, et al. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertility and sterility. 2009; 91(2):456-88. [pubmed]
  7. Rosenfield RL. The Diagnosis of Polycystic Ovary Syndrome in Adolescents. Pediatrics. 2015; 136(6):1154-65. [pubmed]
  8. Witchel SF, Oberfield S, Rosenfield RL, et al. The Diagnosis of Polycystic Ovary Syndrome during Adolescence. Hormone research in paediatrics. 2015; [pubmed]
  9. Martin KA, Anderson RR, Chang RJ, et al. Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline. The Journal of clinical endocrinology and metabolism. 2018; 103(4):1233-1257. [pubmed]
  10. Maslyanskaya S, Talib HJ, Northridge JL, Jacobs AM, Coble C, Coupey SM. Polycystic Ovary Syndrome: An Under-recognized Cause of Abnormal Uterine Bleeding in Adolescents Admitted to a Children’s Hospital. Journal of pediatric and adolescent gynecology. 2017; 30(3):349-355. [pubmed]
  11. Helvaci N, Karabulut E, Demir AU, Yildiz BO. Polycystic ovary syndrome and the risk of obstructive sleep apnea: a meta-analysis and review of the literature. Endocrine connections. 2017; 6(7):437-445. [pubmed]
  12. Elhassan YS, Idkowiak J, Smith K, et al. Causes, Patterns, and Severity of Androgen Excess in 1205 Consecutively Recruited Women. The Journal of clinical endocrinology and metabolism. 2018; 103(3):1214-1223. [pubmed]
  13. Pau CT, Keefe C, Duran J, Welt CK. Metformin improves glucose effectiveness, not insulin sensitivity: predicting treatment response in women with polycystic ovary syndrome in an open-label, interventional study. The Journal of clinical endocrinology and metabolism. 2014; 99(5):1870-8. [pubmed]

PAINE #PANCE Pearl – Women’s Health



Question

31yo, G0P000, is being evaluated in your clinic for infertility. She and her partner have been trying for 3 years to conceive and have not been successful. She report her partner has already had a semen analysis performed and was within normal limits. She reports a regular menstrual cycle, with little to no variability, and normal flow. She has not been on any form of contraception for 3 years. The rest of her past medical history and family history is benign.

What are types of studies that can be used in her infertility work-up?

Ep-PAINE-nym



Cooper’s Ligaments

Other Known Aliasesligamenta suspensoria mammaria

Definitionconnective tissue of the breast that helps maintain structural integrity

Clinical Significance these ligaments run from the clavicle and clavipectoral fascia to the dermis of the skin under the breast and their main clinical function is to support the breast and contribute to the shape and contour of the breast.

HistoryNamed after Sir Astley Paston Cooper (1768-1841), who was an English surgeon and anatomist and trained under Henry Cline and John Hunter before being appointed demonstrator of anatomy in 1789. This was the start to a well-renowned career as professor of anatomy and surgery throughout England culminating in receiving baronetcy in 1820 and becoming sergeant surgeon to George IV in 1828. He made tremendous contributions to the early advancement in surgery including his seminal work on hernias and surgical techniques in the management of vascular aneurysms. He first described his eponymous findings in his text “On the Anatomy of the Breast” in 1840.


References

  1. Firkin BG and Whitwirth JA.  Dictionary of Medical Eponyms. 2nd ed.  New York, NY; Parthenon Publishing Group. 1996.
  2. Bartolucci S, Forbis P.  Stedman’s Medical Eponyms.  2nd ed.  Baltimore, MD; LWW.  2005.
  3. Yee AJ, Pfiffner P. (2012).  Medical Eponyms (Version 1.4.2) [Mobile Application Software].  Retrieved http://itunes.apple.com.
  4. Whonamedit – dictionary of medical eponyms. http://www.whonamedit.com
  5. Up To Date. www.uptodate.com
  6. Cooper AS. On the Anatomy of the Breast. 1840; London.

PAINE #PANCE Pearl – Women’s Health



Question

A 38yo G2P0202 Caucasian woman, with a BMI of 32, presents to your office for evaluation of a “spot” on her breast that she is concerned about. She explains that her great aunt was diagnosed with breast cancer last year at the age of 62 and she is worried. She has not noticed it before, but upon further inquiry states she does not perform self-breast exams very often. She is not currently using any form of contraception (husband has had a vasectomy), but reports using oral contraception pills from age 17-28. She describes her cycle history as regular for her occurring every 28-30 days, lasting 4-5 days with moderate bleeding. She denies any history of abnormal Pap results or any other cancer.

Past Medical History – Hypertension, Anxiety

Medications – Lisinopril 10mg, Escitalopram 10mg

OBGYN History – Menarche at 13, 1st child at 29, 2nd child at 31, breastfed both children for 6 months

Social History – Never smoker, social alcohol

  1. What parts of her history are significant?
  2. What do you specifically want to assess for on your physical examination?
  3. What findings would be considered benign and what would be considered concerning?


Answer

  1. The significant parts of her history are the use of estrogen-containing OCPs alcohol use, and age at time of first child as these have been associated with increased risk of breast cancer. Breastfeeding is actually protective against breast cancer. Her aunt (2nd degree relative) being diagnosed with breast cancer at 62, would only be significant if she was a 1st degree relative under 60 years of age.
  2. Physical examination should include:
    • Inspection – asymmetry, skin changes, and nipple abnormalities
    • Palpation – in a systematic approach with careful attention to the axillary lymph nodes and tail of the breast tissue
  3. Benign masses generally do not skin changes, are smooth, soft to firm, and mobile with well-defined margins. Malignant masses are generally hard, immobile, and fixed to the surrounding skin with poorly-defined margins.
Up-to-Date. 2020

Ep-PAINE-nym



Tail of Spence

Other Known Aliasesprocessus lateralis mammae

Definitiontriangular, tongue-shaped portion of breast tissue that extends superiorly and laterally toward the axilla, perforating the deep axillary fascia where it terminating in close proximity to the axillary lymph nodes.

Clinical Significance Due to location of this breast tissue, many women may not exam this portion of the breast during self-exams. Therefore, given its close proximity to the axillary lymph nodes, providers need to pay close attention to this anatomic region.

Tail of Spence occupies the space where the #3 and #4 nodal regions are

HistoryNamed after James Spence (1812-1882), who was a Scottish surgeon and received his medical doctorate from the Royal College of Surgeons of Edinburgh in 1832. He went on to have a prolific career in teaching anatomy in the classroom and in the dissecting hall at various schools and universities, culminating in serving as chair of systematic surgery and Professor of Surgical Science at Edinburgh University in 1864. Clinically, he served as full house surgeon at the Edinburgh Royal Infirmary for many years leading up to his appointment as Surgeon in Ordinary to Queen Victoria in Scotland in 1865. He was elected as a Fellow of the Royal Society of Edinburgh in 1866 and served as president of the Royal College of Surgeons of Edinburgh from 1867-1869.


References

  1. Firkin BG and Whitwirth JA.  Dictionary of Medical Eponyms. 2nd ed.  New York, NY; Parthenon Publishing Group. 1996.
  2. Bartolucci S, Forbis P.  Stedman’s Medical Eponyms.  2nd ed.  Baltimore, MD; LWW.  2005.
  3. Yee AJ, Pfiffner P. (2012).  Medical Eponyms (Version 1.4.2) [Mobile Application Software].  Retrieved http://itunes.apple.com.
  4. Whonamedit – dictionary of medical eponyms. http://www.whonamedit.com
  5. Up To Date. www.uptodate.com

PAINE #PANCE Pearl – Women’s Health



Question

A 38yo G2P0202 Caucasian woman, with a BMI of 32, presents to your office for evaluation of a “spot” on her breast that she is concerned about. She explains that her great aunt was diagnosed with breast cancer last year at the age of 62 and she is worried. She has not noticed it before, but upon further inquiry states she does not perform self-breast exams very often. She is not currently using any form of contraception (husband has had a vasectomy), but reports using oral contraception pills from age 17-28. She describes her cycle history as regular for her occurring every 28-30 days, lasting 4-5 days with moderate bleeding. She denies any history of abnormal Pap results or any other cancer.

Past Medical History – Hypertension, Anxiety

Medications – Lisinopril 10mg, Escitalopram 10mg

OBGYN History – Menarche at 13, 1st child at 29, 2nd child at 31

Social History – Never smoker, social alcohol

  1. What parts of her history are significant?
  2. What do you specifically want to assess for on your physical examination?
  3. What findings would be considered benign and what would be considered concerning?

PAINE #PANCE Pearl – GYN



Question

Polycystic ovarian syndrome (PCOS) can often be a clinical diagnosis due to the classic distinguishing features of hirsutism, obesity, menstrual irregularities, and infertility. What is the classic relationship between FSH and LH in a patient with PCOS?



Answer

The classic relationship between LH and FSH in PCOS is > 2.5:1.

LH secretion is elevated, while FSH secretion is the same, or even decreased. LH stimulates theca cell proliferation and secretion of androgens, but there is insufficient FSH to stimulate granulosa cells. Although this is classically seen, LH:FSH is NOT used in any diagnostic criteria for PCOS.

Ep-PAINE-nym



Kruckenburg’s Tumor

Other Known Aliases – none

Definitionsecondary ovarian malignancy

Clinical SignificanceMost commonly arising from a gastric adenocarcinoma, but can occur from any metastatic cancer. 80% are bilateral and commonly manifest as pelvic pain, bloating, ascites, or dysparunea. Occasionaly, these tumor can be hormone producing and cause abnormal menstrual bleeding, hirsuitism, or virilization.

HistoryNamed after Friedrich Ernst Krukenberg (1871-1946), who was a German physician and received his medical doctorate from the University of Marburg.  He was actually studying to become a ophthalmologist, when he happend to be spending time in the pathology lab under Felix Marchand.  It was in this department that Krukenberg described a fibrosarcoma of the ovary (using sections from tumors Marchand had found in 1879) and published his findings in an article entitled “Über das Fibrosarcoma ovarii mucocellulare (carcinomatodes)” in 1896 at the age of 25 as part of his doctoral thesis. He spent the rest of career in his hometown of Halle, Germany practicing as a ophthalmologist.


References

  1. Firkin BG and Whitwirth JA.  Dictionary of Medical Eponyms. 2nd ed.  New York, NY; Parthenon Publishing Group. 1996.
  2. Bartolucci S, Forbis P.  Stedman’s Medical Eponyms.  2nd ed.  Baltimore, MD; LWW.  2005.
  3. Yee AJ, Pfiffner P. (2012).  Medical Eponyms (Version 1.4.2) [Mobile Application Software].  Retrieved http://itunes.apple.com.
  4. Whonamedit – dictionary of medical eponyms. http://www.whonamedit.com
  5. Up To Date. www.uptodate.com
  6. F. E. Krukenberg. Über das Fibrosarcoma ovarii mucocellulare (carcinomatodes).  Archiv für Gynäkologie. 1896;50:287-321.

#47 – Obstetrical Screening



*** LISTEN TO THE PODCAST HERE ***



Initial Prenatal Visit

  • Aneuploidy
    • American College of Obstetrics and Gynecology (ACOG) recommends:
      • All women should be offered screening before 20 weeks
      • All women should have the option for having a more invasive procedure instead of screening regardless of maternal age
        • Amniocentesis
        • Chorionic villus sampling
    • Two major categories of screening available
      • Specific maternal serum biomarkers
        • Primarily trisomy 21 and 18
      • Maternal circulation cell-free DNA
        • More sensitive
        • Assesses trisomy 21, 18, 13, and sex chromosome aneuploidies
  • Carrier Screening
    • ACOG recommends:
      • All women should be offered carrier screening for cystic fibrosis, spinal muscular dystrophy, thalassemias, and hemoglobinopathies
      • Fragile X
        • All women with a family history of intellectual disability, developmental delay, or autism
      • Each provider develop a screening strategies for ethnic-specific and panethnic populations
    • If there is a (+) screening test in the mother, then the reproductive partner should be offered screening
  • Standard Panel Laboratory Screening
    • ABO and Rh Screen
      • RhD(-) women should receive prophylactic anti(D)-immune globin at 28-weeks
    • Complete Blood Count and RBC Indices
      • 1st Screen for anemia
    • Documentation of Rubella and Varicella Immunity
      • Rubella IgG
      • Varicella IgG
    • Urinalysis and Urine Culture
      • Urine Protein – establish baseline to compare if patient develops pre-eclampsia or eclampsia
      • Untreated, asymptomatic has higher rates of developing pyelonephritis, pre-term birth
    • HIV Screen
      • ACOG recommends “opt-out” approach
    • Hepatitis B
      • HBsAg regardless of immunization status
    • Chlamydia
      • Nucelic Acid Amplification Test (NAAT) of endocervical/vaginal swab or urine
    • Syphilis
      • Can screen with either a non-treponemal or treponemal test, but a (+) screening test is confirmed with a treponemal test
  • Selective Screening in 1st Trimester
    • Thyroid Function – TSH only
    • Overt diabetes screening
      • Obtain HgbA1C if BMI > 25 (23 in Asian Americans) AND at least one of the following:
        • Gestational diabetes in previous pregnancy
        • HgbA1C > 5.7%, impaired glucose tolerance, or impaired fasting glucose on previous testing
        • 1st degree relative with diabetes
        • African-American, Latino, Native American, Asian American, Pacific Islander
        • History of cardiovascular disease
        • Hypertension (> 140/90 or on medication)
        • Age > 40yr
        • HDL cholesterol < 35 mg/dL or triglyceride > 250 mg/dL
        • PCOS
        • Physical inactivity
        • Other insulin resistance conditions
      • If HgbA1C > 6.5%, then treat as overt diabetes
      • If HgbA1C (-), then screen again at 24-28 weeks
    • Infections
      • Gonorrhea
        • NAAT from endocervical/vaginal swab
      • Hepatitis C
        • High risk patient should be screened with anti-HCV antibody or HCV RNA
      • Tuberculosis
        • Screen with tuberculin skin test or interferon-gamma release assay (IGRA) only if:
          • Suspicion for recent TB infection
          • Immunocompromised
      • Others
        • Toxoplasmosis, trichomonas, herpes simplex, cytomegalovirus, Zika, and Chagas are available for at risk patients or in endemic regions
    • Lead
      • Women with symptoms of lead exposure or risk factors

15-24 Weeks

  • These are not universal and are options available to mothers
  • Quadruple Test
    • Maternal serum alpha-fetoprotein level
    • Unconjugated estriol
    • Human chorionic gonadotropin
    • Inhibin A
  • Fetal ultrasound
    • Can be used to screen for neural tube defects and other fetal anomalies, as well as screen the mother for a short cervical length (< 25mm) that can increased her risk of spontaneous preterm birth

24-28 Weeks

  • Gestational Diabetes Screening
    • Two-Step Approach
      • Step One – Screening
        • 50g, one-hour glucose challenge test REGARDLESS of time of day or last meal
      • Step Two – Diagnostic
        • 100g, three-hour oral glucose tolerance test
          • Traditionally diagnostic after 2 elevated values, but newer data suggests that one may be OK
        • 75g, two-hour oral glucose tolerance test
          • Diagnostic after a single elevated value, but patient must be fasting
Up-To-Date
Up-To-Date
  • Complete Blood Count with iron and folate studies
    • 2nd anemia screening

28-36 Weeks

  • Sexually Transmitted Infection Screening
    • HIV, syphilis, chlamydia, gonorrhea, hepatitis B and C
    • Based on either previous (+) result or evidence of risk factors
Up-To-Date
  • Screen for group B beta-hemolytic streptococcus
    • Vaginal and rectal swabs
    • (+) results treated with intrapartum prophylaxis
CDC – GBS Prophylactic Antibiotic Algorithm
  • Screen for Fetal Growth Restrictions (<10th percentile weight for gestational age)
    • Indicated in third trimester in pregnancies at high risk
      • Infections, fetal anomalies, preeclampsia, gestational HTN and DM, alcohol use, placental/cord abnormalities

References

  1. ACOG Practice Bulletin No. 77: screening for fetal chromosomal abnormalities. Obstetrics and gynecology. 2007; 109(1):217-27. [pubmed]
  2. ACOG Practice Bulletin No. 88, December 2007. Invasive prenatal testing for aneuploidy. Obstetrics and gynecology. 2007; 110(6):1459-67. [pubmed]
  3. ACOG Committee Opinion No. 752: Prenatal and Perinatal Human Immunodeficiency Virus Testing. Obstetrics and gynecology. 2018; 132(3):e138-e142. [pubmed]
  4. Roberts SW, Sheffield JS, McIntire DD, Alexander JM. Urine screening for Chlamydia trachomatis during pregnancy. Obstetrics and gynecology. 2011; 117(4):883-5. [pubmed]
  5. Hughes BL, Page CM, Kuller JA. Hepatitis C in pregnancy: screening, treatment, and management. American journal of obstetrics and gynecology. 2017; 217(5):B2-B12. [pubmed]
  6. ACOG Practice Bulletin No. 190: Gestational Diabetes Mellitus. Obstetrics and gynecology. 2018; 131(2):e49-e64. [pubmed]
  7. Centers for Disease Control.  Group B Strep (GBS).  https://www.cdc.gov/groupbstrep/guidelines/new-differences.html
  8. Bricker L, Medley N, Pratt JJ. Routine ultrasound in late pregnancy (after 24 weeks’ gestation). The Cochrane database of systematic reviews. 2015; [pubmed]

PAINE #PANCE Pearl – GYN



Question

Polycystic ovarian syndrome (PCOS) can often be a clinical diagnosis due to the classic distinguishing features of hirsutism, obesity, menstrual irregularities, and infertility. What is the classic relationship between FSH and LH in a patient with PCOS?