The document discusses endocrine management of female infertility. It outlines the evaluation of endocrine causes of infertility, including diagnostic testing and management of common conditions like PCOS, hyperprolactinemia, hypothyroidism, and Cushing's syndrome. The goal of treatment is to identify and address endocrine abnormalities in order to restore normal hormonal function and fertility. Addressing endocrine disorders is an important part of a comprehensive approach to evaluating and treating infertility in women.

1. Endocrine Management
of Female Infertility
Nemencio A. Nicodemus Jr., MD
Professor, University of the Philippines-College of Medicine
Regent, Philippine College of Physicians
Past President, Philippine Society of Endocrinology, Diabetes & Metabolism
20th ASEAN Federation of Endocrine Societies Congress 2019
November 21, 2019
Philippine International Convention Center

2. Management of
Endocrine Causes
of Female Infertility

3. Learning Objectives
üTo describe the infertility evaluation
for females, focusing on endocrine
causes
üTo outline the diagnostic approach
to endocrine causes of female
infertility
üTo discuss the management of
common endocrine causes of female
infertility

4. Basic Infertility Evaluation
for Females
History
Physical
examination
Pre-
pregnancy
evaluation
Additional
evaluation for
etiology of
infertility
• Diminished
ovarian reserve
• Ovarian
dysfunction
• Tubal factor
• Uterine factor
ACOG Committee Opinion No. 781 American College of Obstetrics and Gynecology. Obstet Gynecol 2019, e377-e384

5. Different
endocrine
disorders
that
potentially
lead to
female
infertility

6. Different
endocrine
disorders
that
potentially
lead to
female
infertility
D. Unuane et al. Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 861–873

7. Hypothalamic lesions that can result in
decreased GnRH secretion and amenorrhea
Developmental
abnormalities cysts
• Craniopharyngioma
(occasionally
intrasellar location)
• Germinoma
• Hamartoma
• Chordoma
• Epidermoid and
Dermoid
Primary tumors of the
central nervous system
• Perisellar meningioma
• Optic glioma
• Ependymoma
Granulomatous
diseases
• Hodgkin’s disease
• Non-Hodgkin
lymphoma
• Leukemic infiltration
• Histiocystosis
• Eosinophilic
granuloma
• Giant cell granuloma
(tumor)
Malignant and systemic
diseases of the central
nervous system
• Neurosarcoidosis
• Wegener’s
granulomatosis
• Tuberculoma
• Syphilis
D. Unuane et al. Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 861–873

8. Different
endocrine
disorders
that
potentially
lead to
female
infertility
D. Unuane et al. Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 861–873

9. Functional pituitary adenomas that
may present with female infertility

10. Effects of Hyperprolactinemia
•Hypogonadism
•Infertility
•Galactorrhea
•Bone loss
• Due to sex-steroid attenuation
• Spinal bone density is decreased by
~25% in women
Gillam MP, et al. E ndocr Rev 27:485–534, 2006
Klibanski A. N E ngl J Med 362:1219–1226, 2010
Schlechte JA. N E ngl J Med 349:2035–2041, 2003
Schlechte J, et al. J Clin E ndocrinol Metab 64:1021–1026, 1987

11. Best test to establish the
diagnosis of hyperprolactinemia
Single measurement of serum prolactin
• When in doubt, sampling can be repeated on a
different day at 15- to 20-min intervals to account for
possible prolactin pulsatility
Serum prolactin level above the upper limit
of normal confirms the diagnosis
The Endocrine Society. J Clin Endocrinol Metab 96: 273–288, 2011

12. Serum Prolactin Ranges In Different Conditions
Am J Obstet Gynecol 1972; 113:14; N Engl J Med 1977; 296:589; Clin Ther 200; 22:1085; Clin Endocrinol 1976; 5:273;
J Clin Endocrinol Metab 1976; 42:1148; J Clin Endocrinoll Metab 42: 181; J Clin Endocrinol Metab 1982; 54:869; Br Med J 1976; 1:1186;
JAMA 1976; 235:2316; Am J Cardiol 1983; 51:1466; J Clin Endocrinol Metab 1985; 60:144.

13. Management of Prolactinoma
• Dopamine agonist
therapy
• Lower prolactin
levels
• Decrease tumor size
• Restore gonadal
function
• Cabergoline
• Preferred
dopamine agonist
• Higher efficacy in
normalizing
prolactin levels
• Higher frequency
of pituitary tumor
shrinkage
The Endocrine Society. J Clin Endocrinol Metab 96: 273–288, 2011

14. Goals and Follow-up During
Dopamine Agonist Therapy
Measure serum prolactin levels every 3 months for the
first year and then annually thereafter
Periodic prolactin measurement starting one month
after therapy
to guide treatment intensification to achieve normal prolactin level
and reversal of hypogonadism
The Endocrine Society. J Clin Endocrinol Metab 96: 273–288, 2011

15. Functional pituitary adenomas that
may present with female infertility

16. Diagnosis of Acromegaly

17. Manifestations of Acromegaly

18. Diagnosis of Acromegaly
Measurement of IGF-1 levels in patients with
• typical clinical manifestations
• pituitary mass
Confirmation of the diagnosis by lack of
suppression of GH to <1 g/L during an oral
glucose load
Katznelson L et al. J Clin Endocrinol Metab 99: 3933–3951, 2014

19. Treatment considerations in the approach
to a patient with acromegaly
Katznelson L et al. J Clin Endocrinol Metab 99: 3933–3951, 2014

20. Biochemical Target Goals For
Patients With Acromegaly
• Age-normalized value
• Signifies control of
acromegaly
Serum
IGF-1
• <1.0 g/L as a therapeutic goal
• Correlates with control of
acromegaly
Random
GH
Katznelson L et al. J Clin Endocrinol Metab 99: 3933–3951, 2014

21. Functional pituitary adenomas that
may present with female infertility

22. Classification of Cushing’s Syndrome
ACTH-DEPENDENT
Pituitary adenoma (Cushing’s disease)
Non-pituitary neoplasm (ectopic ACTH)
ACTH-INDEPENDENT
Iatrogenic (glucocorticoid, megestrol acetate)
Adrenal neoplasm (adenoma, carcinoma)
Nodular adrenal hyperplasia
Primary pigmented nodular adrenal disease
Massive macronodular adrenonodular hyperplasia
Food-dependent (GIP-mediated)
Factitious

23. Clinical presentation of Cushing’s Syndrome:
Typical signs and symptoms
Fat-related
• weight gain
with central
obesity (thin
extremities)
• facial rounding
and plethora
• supraclavicular
fat pads
• dorsocervical
fat pads
Cutaneous
• easy bruising
• fine “ cigarette
paper skin”
• decreased skin-
fold thickness
• poor wound
healing
• purple striae
(usually > 1 cm
in width)
• hirsutism
Muscular
• proximal
muscle
weakness
Emotional and
cognitive
• irritability
• crying
• depression
• restlessness
Young WF, et al. Endocrine Reviews, April 2017, 38(2):103–122

24. Clinical presentation of Cushing’s Syndrome:
Typical signs and symptoms

25. Clinical presentation of Cushing’s Syndrome:
Typical signs and symptoms

26. Co-morbid Conditions Associated
With Cushing’s Syndrome
Hypertension
Osteopenia and osteoporosis
Glucose intolerance and diabetes mellitus
Hyperlipidemia
Opportunistic and fungal infections
Hyperandrogenism (e.g., acne)
Renal lithiasis
Young WF, et al. Endocrine Reviews, April 2017, 38(2):103–122

27. Nieman LK, et al. Journal of Clinical Endocrinology & Metabolism, May 2008, 93(5): 1526–1540
*Measurement of cortisol (urine, serum, or salivary) is the end
point for each of the recommended tests
Case-Detection Tests For
Cushing’s Syndrome

28. Etiology of Cushing’s Syndrome

29. Treatment Options for Cushing’s Syndrome
Nieman LK, et al. J Clin Endocrinol Metab 100: 2807–2831, 2015

30. Medical Treatment of
Cushing’s Syndrome
Steroidogenesis
inhibitor
• Ketoconazole
• Metyrapone
• Mitotane
• Etomidate
Pituitary-directed
• Cabergoline
• Pasireotide
Glucocorticoid
Receptor-directed
• Mifepristone
Nieman LK, et al. J Clin Endocrinol Metab 100: 2807–2831, 2015

31. Treatment Goals For
Cushing’s Syndrome
Normalizing cortisol levels or action at its
receptors
Eliminate the signs and symptoms of CS
Treating co-morbidities associated with
hypercortisolism
Nieman LK, et al. J Clin Endocrinol Metab 100: 2807–2831, 2015

32. Different
endocrine
disorders
that
potentially
lead to
female
infertility

33. Nervousness/Tremor
Mental Disturbances/ Irritability
Difficulty Sleeping
Bulging Eyes/Unblinking Stare/
Vision Changes
Enlarged Thyroid (Goiter)
Menstrual Irregularities/
Light Period
Frequent Bowel Movements
Warm, Moist Palms
First-Trimester Miscarriage/
Excessive Vomiting in Pregnancy
Hoarseness/
Deepening of Voice
Persistent Dry or Sore Throat
Difficulty Swallowing
Palpitations/
Tachycardia
Impaired Fertility
Weight Loss or Gain
Heat Intolerance
Increased Sweating
Family History of
Thyroid Disease
or Diabetes
Signs and Symptoms of Hyperthyroidism
Sudden Paralysis

34. Tiredness
Forgetfulness/Slower Thinking
Moodiness/ Irritability
Depression
Inability to Concentrate
Thinning Hair/Hair Loss
Loss of Body Hair
Dry, Patchy Skin
Weight Gain
Cold Intolerance
Elevated Cholesterol
Family History of Thyroid Disease or
Diabetes
Muscle Weakness/
Cramps
Constipation
Infertility
Menstrual Irregularities/
Heavy Period
Slower Heartbeat
Difficulty Swallowing
Persistent Dry or Sore Throat
Hoarseness/
Deepening of Voice
Enlarged Thyroid (Goiter)
Puffy Eyes
Clinical Features of Hypothyroidism

35. The work-up of an infertile women with
potential thyroid problems
TSH, TPOAb
TSH>2.5
mIU/L*
Start LT4
before
COH/ART
TSH 0.27 – 2.5
miU/L
TPO (-)
Follow-up
after COH0
TPO (+)
Start LT4
before
COH/ART
TSH<0.27
mIU/L
Ft4, Ft3, TRAb
ATD or
Surgery
D. Unuane et al. Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 861–873

36. Different
endocrine
disorders
that
potentially
lead to
female
infertility

37. One of the most common conditions in
reproductive aged women
•8-13% prevalence
•Up to 70% of
affected women are
undiagnosed
Azziz, R., et al. Journal of Clinical Endocrinology & Metabolism, 2006. 91(11): p. 4237-45.
Diamanti-Kandarakis, E., H. Kandarakis, and R. Legro. Endocrine, 2006. 30(1): p. 19-26.
March, W., et al. Human Reproduction, 2010. 25(2): p. 544-51.
Bozdag, G., et al. Hum Reprod, 2016. 31(12): p. 2841-2855
PCOS

38. Diagnosis of PCOS: Any two
Oligo- or
anovulation*
Hyperandro
genism*
Polycystic
ovaries
* If both present, ultrasound is not necessary for diagnosis
Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group 2004. Fertil Steril 81:19–25

39. How to assess biochemical
hyperandrogenism?
Calculated free testosterone, free androgen
index or calculated bioavailable testosterone
High-quality assays: liquid chromatography–
mass spectrometry (LCMS) and
extraction/chromatography immunoassays
Androstenedione and
dehydroepiandrosterone sulfate (DHEAS), if
total or free testosterone are not elevated
Teede HJ, et al. on behalf of the International PCOS Network. Human Reproduction, pp. 1–17, 2018

40. Assessment of Clinical
Hyperandrogenism
Acne Alopecia Hirsutism
Teede HJ, et al. on behalf of the International PCOS Network. Human Reproduction, pp. 1–17, 2018

41. Management to improve reproductive
and obstetric outcomes in PCOS
Necessary in all
• Blood glucose, weight, BP, smoking, alcohol, diet,
exercise, sleep and mental, emotional and sexual health
need to be optimised
1st line pharmacological agents
• Ovulation induction agents like letrozole, metformin
and clomiphene citrate
2nd line pharmacological agents
• Gonadotrophins
International evidence-based guideline for the assessment and management of polycystic ovary syndrome.
Copyright Monash University, Melbourne Australia 2018

42. Endocrine Work-up Of Infertility
Infertility
TSH and anti-TPO
Ab
FSH, estradiol
PRL
History and PE
D. Unuane et al. Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 861–873

43. Endocrine Work-up
Of Infertility
FSH, estradiol
FSH ↑ estradiol ↓
Hypergonadotropic
hypogonadism
Primary ovarian
disease
FSH ↓ estradiol ↓
Hypogonadotropic
hypogonadism
Exclude
hypothalamic
pituitary disease
FSH N estradiol N
Testosterone: PCOS
Exclude endocrine
tumors
(ovarian/adrenal)
D. Unuane et al. Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 861–873

44. Summary
• The evaluation of female infertility must
consider etiologies other than ovarian
and uterine abnormalities
• There are common endocrine disorders
that manifest with infertility due to
hormonal changes
• The management of endocrine causes
of female infertility require prompt
identification and targeted management

45. Take care of the women,
take care of the future generation!