Endocrinologists Role In Infertility Management

Sidika E. Karakas, MD

Professor and ChiefDivision of Endocrinology, Diabetes and Metabolism

University of California, Davis

Thoma et al. Fertility and Sterility 99:1324, 2013

ALL WOMEN(n = 270)

NULLIPAROUS WOMEN

(n =139)

Infertility: Inability to become pregnant after 12 months of trying

Prevalence: 7.4% among married women in the United States

What is typical?

• Average age of menarche in USA is 12 y

• >90% females >15 y have >10 menses/y

Amenorrhea

• Primary—Absence of menses by age 16 y

• Secondary—Absence of menses for >6 mo

Oligomenorrhea

• Period intervals >35 days

• 4 to 9 periods/ year

What is our job as endocrinologists?

I. Ruling out non-endocrine infertility

II. Correct diagnosis of endocrine causes

III. Optimizing hormonal and metabolic milieu

for ovulation

Ruling out non-endocrine infertility

Identifying ovulatory women

by measuring progesterone during the 3rd week of

menstrual cycle (typically > 4)

Infertile Couple

Semen Analysis

• Volume: 2 – 5 ml

• Sperm count: 40 – 300 million

• Motility & velocity: > 50% active

• Morphology: > 30% normal

• Liquefaction: liquid gel

liquid in 20 min (otherwise seminal vesicle pathology)

• Fructose: None—Obstruction of

ejaculatory duct; absence of vas deference or seminal vesicles

• Culture

Correct Diagnosis of Endocrine Causes

PCOS-Centric View

PCOS

90%

Hypothalamic Weight loss; systemic illnessKallmann’s SyndromeHypogonadotropic

hypogonadism

PituitaryHyperprolactinemiaHypopituitarism

Ovary 5%Primary ovarian failure

5%

PCOS is responsible for 90% of anovulatory infertility

What is PCOS?

Roe, Rev Obstet Gynecol. 2011

PCOS Phenotypes

A) Hyperandrogenism + Anovulation + PCO

B) Hyperandrogenism + Anovulation

C) Hyperandrogenism + PCO

D) Anovulation + PCO

What is our practice?

Endocrinologists

(n = 138)

Gynecologists

(n = 172)

Menstrual Irregularity 70% 50%

PCO on Ultrasound 14% 60%

Uses NIH or Rotterdam for Dx 40% 15%

My screening tests for PCOS

AMH Testosterone panel (total-,

bioavailable- and free- testosterone plus SHBG)

Ovaries in PCOS

• ovarian volume ≥ 10 ml

• ≥ 12 follicles; each 2–9 mm

• subjective appearance of PCO cannot be substituted

Anti-Mullerian Hormone (AMH)

• Glycoprotein

• Produced by granulosa cells of primary, pre-

antral and early antral follicles (2-7 mm)

• NOT by larger or atretic follicles

• Indicator of ovarian reserve

AMH

– Age 10-21: Average = 3 ng/mL

– > 5 ng/ml ---PCOS

– < 0.8 ng/ml ---Menopause

– > 1.3 ng/ml---Successful IVF

– 30% decrease during oral contraceptive therapy

AMH IS ELIMINATING THE NEED FOR TRANSVAGINAL US

• Free testosterone 2%

• Albumin bound 50%

• SHBG bound 44%

• Bioavailable testosterone---Testosterone not bound by SHBG

Why measure free or bioavailable

testosterone?

Total testosterone does not reflect

androgen exposure

Age 10-21: Average = 3 ng/mL>5 ng/ml ---PCOS

< 0.8 ng/ml ---Menopause

> 1.3 ng/ml---Successful IVF

Age 10-21: Average = 3 ng/mL>5 ng/ml ---PCOS

< 0.8 ng/ml ---Menopause

> 1.3 ng/ml---Successful IVF

Effect of Oral Contraceptive on Testosterone Bioavailability

Before After

Case A

T: 93 (9 – 55 ng/dL)

SHBG: 40 (30 – 135 nmol/L)

Bioavailable-T: 39.7 (4.1 – 25.5 ng/dl)

Free-T: 14.0 (1.3 – 9.2 pg/mL)

31 yo female

Irregular periods in the past. IUD placement 5 years ago and no periods while on IUD. Oral contraceptives after IUD till 9/2016. Since then q 30 day

periods; LMP 7/1/17; next cycle expected on 8/1/17

Hirsutism: On abdomen, chest, chin and lip. Waxes chin once a month. Electrolysis for chest and abdomen-- last session on 7/24. Hair on arms that are darker; normally blonde.

Case B

T: 25 (9 – 55 ng/dL)

SHBG: 80 (30 – 135 nmol/L)

Bioavailable-T: 6.9 (4.1 – 25.5 ng/dl)

Free-T: 2.3 (1.3 – 9.2 pg/mL)

31 yo female

Heavy periods was referred for PCOS. No hirsutism. After seeing her labs, I questioned how was her diagnosis made; her

response was: The diagnosis was based on my symptoms and history. Heavy

periods run in my family. My endocrinologist didn't do much except give the meds based on the “PCOS pathway treatment plan .”

Necessary and Sufficient

– AMH

– Bioavailable testosterone

– DHEAS—to r/o adrenal androgen excess

– 17OHP—to r/o CAH (21OH deficiency)

– Prolactin—to r/o prolactinoma

– FSH—to r/o premature ovarian failure

– Cortisol –Only if there are supraclavicular fat pads

CASE 1

• 19 yo WF

• CC: Last period 17 mo ago

• Menarche 13 yo

• Irregular to start with: approximately q 3 mo

• No oral contraceptives

• No pregnancies

• No hirsutism

• No breast discharge

CASE 1 continued

• Gained 18 kg in the last 2 y

• Diets: Zone diet; lost 11 kg 3 y ago

• Hearing loss in left ear, bone abnormalities

• Ht: 1.72 m; Wt: 108.8 kg BMI: 36.5

• No hirsutism

• No acanthosis or skin tags

• No dorsoclavicular fat pads, no webbing

• Normal breasts; no discharge

AMH: < 0.003

Testosterone: 23 (N < 55)

AMH: < 0.003

Testosterone: 23 (N < 55)

FSH: 50.2

Karyotyping results

Fragile X• X-linked disorder

• Decreased or absent fragile X mental retardation

protein (FMRP) due to a loss-of-function mutation in the fragile X mental retardation 1 (FMR1) gene

• Caused by expansion of a trinucleotide (cytosine-guanine-guanine, CGG) repeat at the 5' untranslated

region

• Expansion of >200 repeats: Full mutation

• Expansion between 50 -200 repeats: Pre-mutation

• Pre-mutation is associated with premature ovarian failure

CASE 2

18 yo female

• CC: Only 1 period in entire life, during 7 th grade

• Normal breast growth, no discharge

• Shorter than siblings (4’11’’)

• Normal mental development

• Premature birth

• Cyst in the neck with permanent swelling, no

hypothyroidism

Case 2 continued

• Ht: 4’8’’; Wt: 134 lb; BMI: 34.8

• Neck asymmetrical, swollen on the R

• No facial hair

• Acanthosis + in the axilla

• Breast exam: Well developed; exam was not

done (mother & sister are in the room)

• White striae in the abdomen

AMH: 2.1

Testosterone: 11 (N < 55)

– Bioavailable-T: 5.5 (<20.6)

– Free-T: 1.8 (<7.4)

Endocrine Testing

• HCG : Negative

• FSH: 6.5

• Prolactin: 194 (<19.5)

• TSH: 1.22

• Growth hormone: 0.12

(0.05-8)

• IGF-1: 277 (165-585)

What is our job as endocrinologists?

• Optimizing hormonal and metabolic milieu for ovulation

PCOS—Two Sided Coin

Hormonal

Ovarian DysfunctionMetabolic

Insulin Resistance

Insulin Resistance in PCOS

PCOS women maintain normal glucose tolerance at the expense of hyperinsulinemia

By age 40 y, 1 out of 5 PCOS women develops T2 diabetes

Physical Clues for Insulin Resistance

Acanthosis and Skin Tags

Other Clues for Insulin Resistance

in PCOS Women with Normal Glucose Tolerance

8.1

1.4

27.4

6.9

5558

1.93.7 2.9

31.6

13.1

49

38

5.91.9

5.6

39.9

24.4

40

25

10.6

0

10

20

30

40

50

60

70

ISIMatsuda HOMA BMI Fasting

Insulin

HDL-C SHBG hs-CRP

S. Karakas et a. Diabetes Care 2010

HgBA1 > 5.7% is a Very Useful Marker in PCOS

HgBA1 < 5.7

(n = 25)

HgBA1 >5.7

(n = 23)

P value

Age (years) 31.1 ± 1.1 35.1 ± 1.1 0.039

Fasting glucose (mg/dl) 91.5 ± 0.9 99.6 ± 2.3 0.028

Adiponectin (ng/ml) 12.4 ± 0.9 8.8 ± 0.7 0.023

FS-IVGTT

SI 4.2 ± 0.6 2.0 ± 0.2 0.020

DI 1901 ± 217 1014 ± 82 0.011

CVD risk factors

Triglyceride (mg/dl) 92.6 ± 4.4 125.3 ± 9.5 0.018

hs-CRP (ng/ml)

FABP4 (ng/ml)

2.1 ± 0.1

34.8 ± 2.9

4.76 ± 0.5

58.5 ± 4.9

0.003

0.021

R. Mortada et al. Endo Prac 2013

How to reduce insulin resistance?

• Weight loss (7%)

• Exercise (150 min /week)

• Metformin (1,500 mg/d)

• Acarbose (>50 mg/tid-AC)

• Herbals?

Effects of Weight Loss on Fertility

• 33 PCOS patients

• 25 lost 5% weight

• 11 of these lost >10%

• 15 women ovulated

• 10 became pregnant

P.G. Crosignani et al. Human Repro 18:1928, 2003.

Effect of Life Style Changes on AMH and Ovarian Function

DIET EXERCISE DIET plus EXERCISE

BMI 35.4±4.9 32.9±5.5*** 34.8±5.2 34.1±5.7* 38.1±7.0 36.9±8.0***

T (ng/mL) 0.51±0.22 0.40±0.19* 0.44±0.18 0.44±0.21 0.50±0.21 0.45±0.19

FT (pg/mL) 16.3±7.4 11.0±5.4** 13.0±6.1 12.0±6.6 17.2±9.0 12.6±6.8

AMH (ng/mL) 10.4±6.2 7.7±5.3** 9.2±5.5 9.2±5.9 9.9±6.0 8.5±5.6

Follicle number 12.4±3.9 9.4±2.4* 13.2±4.6 10.5±3.2** 12.8±4.7 10.1±3.4*

Ovulation 0 5/14(36%) 0 6/17 (35%) 0 4/12 (33%)

Nybacka et al. Fertil Steril 100: 1096, 2013

Duration: 4 months

Diet: -600 kcal restriction

Exercise: 45- 60 min; 2-3 times/wk

My Practice

METFORMIN (6-9 months)

Oral Contraceptive 3-4 months

Trying for pregnancy &

Progesterone monitoring

Clomiphene, Metformin or Both for Infertility in PCOS.

Legro et al. NEJM, 2007

Baseline Characteristics of 626 PCOS Women

Age (Years)28.1± 4

BMI35.3±8.6

Length of trying (mo)40.4±35.8

No Treatment262 (42%)

Previous Treatment374 (58%)

Treatment Outcomes

Metformin

(208)

Clomiphene

(209)

Combination

(209)

Ovulation 296/1019 (29%) 462/942 (49%) 582/964 (60%)

Conception 25/208 (12%) 62/209 (30%) 80/209 (38%)

Live Birth 15/208 (7%) 47/209 (23%) 56/209 (27%)

Pregnancy Loss 10/25 (40%) 16/62 (26%) 24/80 (30%)

Patient population

Obese Trying for a long time

Previously treated

European and Australian Experience

• In PCOS women with BMI ≤ 30 kg/m2 there is no difference between metformin vs. Clomiphene

Palomba S, Pasquali R, Orio F Jr, Nestler JE.

Clomiphene citrate, metformin or both as first-step approach in treating

anovulatory infertility in patients with polycystic ovary syndrome (PCOS):

A systematic review of head-to-head randomized controlled studies and meta-

analysis.

Clin Endocrinol (Oxf). 2009 Feb;70(2):311-21

Clomiphene vs. Aromatase Inhibitors

Ovulation Induction Protocols