19/05/2021
Female hypogonadism Dr. Kalani Kahapola Arachchige 14th May 2021
1
Topics covered
Definition Normal physiology Causes of Primary and secondary Amenorrhea and approach to laboratory testing with case presentation
2
1 19/05/2021
Hypogonadism – Definition
Hypogonadism is a clinical syndrome caused by disruption of any level of the hypothalamic –pituitary-gonadal axis which results in hormone deficiency.
Main clinical presentation amenorrhoea
3
Understanding pathology
• Two categories based on underlying aetiology • Primary hypogonadism (hypergonadotrophic hypogonadism) – gonadal failure • Secondary hypogonadism (hypogonadotropic hypogonadism) – dysfunction within the hypothalamus and/or pituitary
Primary hypogonadism Secondary hypogonadism
FSH FSH
LH LH
Estradiol Estradiol
Progesterone Progesterone
4
2 19/05/2021
Definitions continue
Female hypogonadism presents as In pre pubertal girls as – delayed puberty or Primary amenorrhea Post pubertal girls/women – Secondary amenorrhea and other associate symptoms and signs of the underlying aetiology.
Practical approach to female hypogonadism would be review aetiology based on clinical presentation Primary amenorrhea – absence of menarche by age 15 years or 3 years post breast development (delayed pubertal development or post secondary sexual characteristics) Secondary amenorrhea – absence of menses for > 3months in women with previously regular menstrual cycles or six months in women with irregular menses
Diagnosis require comprehensive assessment of clinical history, evaluation of signs of symptoms , complete physical examination and laboratory testing
5
Understanding normal physiology - menstrual cycle
Menstruation is the cyclic, orderly sloughing of the uterine lining, in response to the interactions of hormones produced by the hypothalamus, pituitary, and ovaries.
4 distinct phases
Menstruation
Follicular phase
Luteal phase
Important to understand normal cycle and to aid with interpretation of the results
6
3 19/05/2021
Reference intervals on Abbott Alinity
7
Hormone Testing
Immunoassay
Age-specific and method specific ref intervals for LH and FSH
Heterophile antibodies
Inter-laboratory variation – despite international reference calibration preparations (WHO) Measure immunoreactivity not bioactivity -Mutations in ß subunit – changes in immunoreactivity Cross reactivity especially LH with hCG
Diagnosing delayed puberty Sensitive assays for LH (and oestradiol and testosterone\to detect pre-pubertal levels. Eg. Prepubertal LH < 0.1 IU/L , Pre-pubertal E2 <1 pg/L (undetectable with most routine assays )
8
4 19/05/2021
Case presentation …..
9
Case 1
20 yr old female Menarche age 12 , regular cycles initially, amenorrhoeic for 2 years now Normal secondary sexual characteristics Play net ball in school, cross country running, swimming, running Slim built Normal diet (some concerns of body image and anxiety) BMI – 20 HCG – Negative FSH 5, LH 2, E2 <85, Prog <1 10
5 19/05/2021
Secondary hypogonadism low-normal FSH & LH, low-normal E2
11
Investigations of patient with secondary hypogonadism
Prolactin TSH with fT4 Testosterone, SHBG and FAI Other androgens – Androstenedione , DHEAS , 17 OH progesterone +/- AMH +/- 24 hr urine cortisol level
12
6 19/05/2021
Functional Hypothalamic Amenorrhoea(FHA)
Accounts for 30% of women associated with secondary amenorrhoea
Form of chronic anovulation that is not due to identifiable organic cause (absence of anatomical or organic pathology).
Typically associated with Stress/ mood disorder Weight loss/ low energy
Driven by the reduction in GnRH resulting low LH and FSH levels which are insufficient to maintain full folliculogenesis and ovulatory ovarian function
Individual sensitivity to reproduction when exposed metabolic and psychosocial stressors can vary
13
Case 2
27 yr. old female
OCP from age 16 yrs. to 24 yrs.
Off pill amenorrhea for 3 years on and off “hot feeling”
History of Bulimia,
Current BMI 20
Concerns about future fertility – recent relationship break down
Lawyer
Exercise – 4-5 times a week at the gym.
14
7 19/05/2021
Case 2 - Results
14/06/2017 15/07/2017 FSH 14 (2-10) 5 LH 1.5 Oestradiol 160 Progesterone <1 Total 1.0 testosterone SHBG 87 Prolactin 80 TSH 2.5 AMH <0.1
15
AMH – anti Mullerian hormone
16
8 19/05/2021
Case 2 - Results
14/06/2017 15/07/2017 3/11/2017 FSH (1-10) 14 5 70 LH 1.5 10 Oestradiol 160 <100 Progesterone <1 <1 Total 1.0 testosterone SHBG 87 Prolactin 80 TSH /fT4 2.5/ 12 AMH <0.1
Premature ovarian insufficiency
17
Case 3
36 yr. old with no menstrual cycles for 5-6 months with recent onset of hot flushes .
Recently married and concern about fertility
22/11/16 21/01/17 FSH 84 (1-10)14 LH 30 (1-10) 7 Oestradiol <100 510 Progesterone 2 21
18
9 19/05/2021
Premature ovarian insufficiency
Premature ovarian insufficiency- amenorrhoea due to the loss of ovarian function before 40 years of age.
Primary ovarian insufficiency affects 1 in 10,000 women by age 20, 1 in 1000 by age 30, and 1 in 100 by age 40.
Criteria to establish the diagnosis of primary ovarian insufficiency
Younger than 40 years of age
Oligo/amenorrhea lasting 4 months
Two FSH levels in the menopausal range, obtained at least a month apart
19
Causes of POI Genetic causes ~50%
Turners syndrome – complete or partial loss of an X chromosome
Fragile X premutation
Other X chromosome defects
Genes in 46 XX gonadal dysgenesis - STAG3, ESR2 Chemotherapy and radiation ~ 40% Autoimmune ovarian destruction
Polyglandular autoimmune syndrome type 1 & 2‐ Addison’s disease and hypoparathyroidism Metabolic –Galactosemia , type 1 DM, Resistant ovary syndrome ‐auto‐antibodies to gonadotrophin receptor in 46 XX females‐ primary amenorrhoea Idiopathic ~ 5%
20
10 19/05/2021
Investigation of premature ovarian insufficiency
Investigation Cause Genetic Karyotype, FMR-1 premutation Autoimmune Thyroid (TPO ab), Adrenal ab, Coeliac autoantibodies, Ovarian antibodies non-specific
Long tern sequelae Fasting lipids, FBG or HbA1c, 25OH • CVD risk vitamin D, Calcium, Phosphate, U&E • Bone health
Fertility AMH Specific cause Turner syndrome complications/Autoimmune disease
21
Case 4 Case 5
30 yr. old 29 yr old Menarche age 10 , irregular cycles Menarche age 13 yrs. and amenorrhea for 1 year Irregular menstrual cycles Acne as a teenager , mild hirsutism Amenorrhoea for 3 months , hair loss Acne since age 8-9 yrs. , Hirsutism , BMI -27 clitoromegaly BMI 20
22
11 19/05/2021
Investigation findings
Case 4 Case 5
FSH 5, LH 4, E2 119, Prog <1 , HCG –ve Day 10 – FSH-5 , LH -9, E2 and Prog 3, HCG –ve Prolactin- N , TSH – N Prolactin, TSH – normal Testosterone 2.1 nmol/L Testosterone 2.5nmol/L SHBG- 19 nmol/L (30-120) SHBG -77 nmol/l (30-120) FAI – 11 (<6) Androstenedione 10.5 (1-11.5) FAI -3 (<6) 17 OH progesterone 1.0 (<2) Androstenedione -15.5 nmol/L (0.9-7.5) DHEAS 8 umol/L(1.65-9.15) 17 OH progesterone -33.4 (0.2-2.0) Pelvic USG – PCOM DHEAS -17.3 (2.6-9.2)
PCOS Late onset Congenital adrenal hyperplasia
23
PCOS diagnosis and investigation
It is an endocrine condition primarily associated with alterations in testosterone and insulin hormones. Rotterdam Criteria for diagnosis of PCOS are as follows:
1. Oligo‐ovulation or anovulation
2. Clinical or biochemical signs of hyperandrogenism
3. Polycystic appearing ovaries on ultrasound
Characteristics Phenotypes ABCD Hirsutism/Hyperandrogenism XXX
Ovulatory dysfunction XX X Polycystic ovaries X XX
24
12 19/05/2021
CAH – congenital adrenal hyperplasia
Autosomal recessive disorders
21‐hydroxylase deficiency
due to mutations in the CYP21A2 gene
accounts for approximately 95 percent of cases.
Classic CAH ‐ present neonatal period and early infancy with adrenal insufficiency and salt wasting or in the first few years of life with virilization. Females have ambiguous genitalia.
Nonclassic CAH (NCCAH) is a less severe form of the disorder in which there is 20 to 50 percent 21‐hydroxylase enzyme activity
25
Diagnosis
Basal 17 OH progesterone level in follicular phase
Immunoassay
LCMS
Different cut off’s and diagnostic accuracy can be an issue Short synacthen test with concurrent 17 OH progesterone Genetic testing
26
13 19/05/2021
Case 6
30 year old female presenting to GP with history of primary amenorrhoea Phenotypically female with breast development. Diagnosis made by a chemical pathologist post review of blood test results
27
Case 6
Blood test results
Test Result 5/11/18 FSH 5 U/L (4-12) Roche LH 20U/L (2-13) Estradiol 192 pmol/L (46-607) Progesterone 0.8 nmol/L Prolactin 204 mIU/L (102-496) TSH 0.93mU/L fT4 12pmol/L LFT, UEC, All normal Iron studies ,BSL HCG Negative
28
14 19/05/2021
Case 5
Test Results Testosterone 48.6 nmol/L (0.3-1.7) SHBG 116 nmol/L (32-128)
AMH 1065 pmol/L (13.1-53.8) male ( 257-1371 T1)
Karyotype 46XY
Complete Androgen insensitivity syndrome !
29
Complete androgen insensitivity syndrome(testicular feminization syndrome)
Estimated prevalence of CAIS ranges from 1:20400 to 1: 99000 genetic males X linked disease – Mutation in Androgen receptor gene XY genotype and variable phenotype, depending on the degree of receptor defect. Testicular feminization: the most severe form of androgen resistance syndrome; female phenotype but a blind vaginal pouch. Testosterone receptors are non-functional or absent.
30
15 19/05/2021
Clinical manifestations
Clinical features of CAIS Usually presents with primary amenorrhoea Infants - inguinal hernia , labial lumps Normal breast development Normal pubertal growth spurt at the appropriate age Pubic and axillary hair is absent or sparse No uterus, cervix & proximal vagina (AMH effect) Blind-ending vagina Taller than genetic females Low BMD overall but no increase fracture risk
31
Diagnosis
Karyotype – 46 XY Biochemistry – age is important Testosterone – normal or higher - for men or boys at puberty LH is inappropriately increased (androgen R at hypothal-pit level) FSH & inhibin – normal Serum E2 higher than expected for men but lower than in women SHBG is similar to that of in women AMH levels are higher than in male infants (indicates presence of testes and is due to uninhibition of sertoli cells) can be normal as well Management: Testes should be removed after puberty because of the increased risk of a malignant transformation due to cryptorchidism.
32
16 19/05/2021
Amenorrhea
Rule out pregnancy FSH, LH , E2, prog
Primary Secondary hypogonadism hypogonadism (Ovarian) Low nomal FSH & Raised FSH, LH, low LH , Low normal E2 E2
Prolactin, TSH &fT4, testosterone, SHBG Investigate for POI
33
In Summary
Female hypogonadism present clinically as primary or secondary amenorrhoea
Laboratory testing has a central role in determining the underlying aetiology
Knowledge and understanding of the biochemical changes vital in diagnosis
34
17 19/05/2021
Thank you
35
Understanding normal physiology – female pubertal development
1. Production of gonadotrophin‐releasing hormone (GnRH) from the hypothalamus.
2. Hypothalamic GnRH stimulates pituitary to produce LH and FSH.
3. Circulating LH and FSH stimulate gonads to produce sex hormones (oestrogen). Kiss peptin 4. Development of secondary sexual characteristics = full reproductive competence.
36
18