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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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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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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

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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

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Definition and Diagnostic Criteria

• Adults
  • Rotterdam Criteria
    • 2 of 3 following criteria:
      • Anovulation
      • Hyperandrogenism
      • Polycystic ovaries

• Adolescents
  • Developed in 2015 and consist of otherwise unexplained persistent hyperandrogenic oligo-anovulatory menstrual abnormality based on age and stage appropriate standards

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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

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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 (1^st 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 (2^nd 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 (3^rd 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

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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

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The Cottage Physician (1893)

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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]

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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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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?

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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.