Author: Kristopher Maday PA-C

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Stein-Leventhal Syndrome

Other Known Aliases – Polycystic Ovarian Syndrome (PCOS)

Definition – clinical syndrome of hyperandrogenism, oligoanovulation, and polycystic ovaries.

Clinical Significance – PCOS is the most common cause of female infertility and should be investigated in women as part of the infertility workup. Women with PCOS can also have acne, hirsutism, menstrual irregularity, virilization, obesity, insulin-resistance, and metabolic syndrome. It is typically diagnosed in adolescents due to the phenotypic syndromic features.

History – Named after Irving F. Stein, Sr. (1887-1976) and Michael L. Leventhal (1901-1971) and both received their medical doctorates from Rush Medical College in 1912 and 1924 respectively. Both met while practicing at Michael Reese Hospital in early to mid-1900s. They presented a case report of 7 cases of amenorrhea, hirsutism, obesity, and enlarged polycystic ovarias in 1934 at the Central Association of Obstetrics and Gynecologists. They published these findings one year later in 1935 in an article entitled “Amenorrhea associated with bilateral polycystic ovaries” in the Americal Journal of Obstetrics and Gynecology. It should be noted that Russian gynecologist S.K. Lesnoy first described polycystic ovaries in 1928, but not the complete syndrome.

  • Stein
  • Leventhal

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. Baskett TF. Eponym and Names in Obstetrics and Gynaecology. 3rd Ed. Cambridge, UK. Cambridge University Press. 2019.
  7. Powell JL. Powell’s Pearls: Irving Freiler Stein, MD (1887-1976) and Michael Leo Leventhal (1901-1971). FPMRS. 2008;14(5):413-414. [article]
  8. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. AJOG. 1935;29(2):181-191. [article]

PAINE #PANCE Pearl – Women’s Health

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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?

Answer

  1. Assessment of Ovulatory Function
    • Mid-luteal phase serum progesterone typically drawn seven days prior to the start of her menstrual cycle
      • > 3 ng/mL = recent ovulation
  2. Assessment of Ovarian Reserve
    • Anti-müllerian hormone (AMH) reflects the size of the follicle pool
    • Clomiphene citrate challenge test (CCCT)
      • 100mg clomiphene on day 5-9 and measurement of day 3 and day 10 FSH and day 3 estradiol
  3. Assessment of Fallopian Tube Patency
    • Hysterosalpingogram
  4. Assessment of Uterine Cavity
    • can be assessed via HSG, but can also be assessed with a saline-infusions sonohysterography or hysteroscopy

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Naegele’s rule

Other Known Aliases – estimated date of delivery

Definition – estimation of delivery assuming a 280 day gestation period and is calculated from the FIRST day of the last menstrual cycle by adding 1 year, subtracting 3 months, and adding 7 days.

Clinical Significance – this is a quick and easy estimation of the delivery date for planning purposes and is used in most apps and delivery wheels. In the age of ease of ultrasound, direct measurement is becoming the standard, but this is still a very important calculation to remember.

History – Named after Franz Karl Naegele (1778-1851), who was a German obstetrician and received his medical doctorate from the the University of Bamberg. He had a very successful practice in Barmen, Germany, before he went on to become full professor of obstetrics in 1810 at the University of Heidelberg. He first mentioned his rule, and credited Hermann Boerhaave who first mentioned it in 1744, in a manuscript in 1812, but was given the eponym by Gunning Bedford, professor of obstetrics and diseases of Women and Children at the University of New York, in 1872.

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. Baskett TF. Eponym and Names in Obstetrics and Gynaecology. 3rd Ed. Cambridge, UK. Cambridge University Press. 2019.
  7. Baskett TF, Nagele F. Naegele’s Rule: a reappraisal. BJOG. 200;107(1):1433-1435.
  8. Naegele FC. Erfahrungen und Abhandlungen aus dem Gebiethe der Krankheiten des Weiblichen Geschlechtes. Nebst Grundziigen einer Methodenlehre der Geburtshiilfe. Mannheim: Loeffler, 1812: 280-281
  9. Bedford GS. The Principles and Practice of Obstetrics. 5th Edition. New York William Wood and Co, 1872:306.

#56 – Polycystic Ovarian Syndrome

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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

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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?

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Cooper’s Ligaments

Other Known Aliases – ligamenta suspensoria mammaria

Definition – connective 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.

History – Named 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

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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