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* s AMENORRHEA SECOONDAQY TO VOL~XTARE’ u

- - R. LeonGraharn, Captain, USAF, MC, 3

- David L, Grimes, Captain, USAF, MC, J

R. Don Garxbrell, Jr., Colonel, USAF, MC,

Preslentrd at the Ap4 Forces District Meet‘ Americar? College of - Obstetricians c and Cyne New Orleafis, Louisiana, 9-13 October 197;

The opinions or assertions contained herein are those are zot to be construed as official or reflecting the vi States Air Force or the Depi?.rtxn -it of Defense.

AIR1.961126.02Op

AASTMCT

Patients with voluntsx w e i g h t loas not only may develop c

secondary amenorrhea like women with anorexia nervosa but

apparently a lso have similar endocrine findings. S i x young

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women who voluntxrilydietedtolose frow. 13-50pounds, includ-

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ing 4 f rom an obese weight, were evaluated because of no cervi-

cal mucus ferning, hypoestrogenic vzginal smears, and failure

to have withdrawalmenses from a progestogen. S e r u m FSH w a s

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normal in all while 4had normal serum LH and 2 hadlow serw-’ \

LH. T4 and/or T 3 uptake w a s normal in all. The pituitary-

adrenal axis w a s apparently intact since baseline urinary steroids

were normal as w a s the response to both ACTH and metyrapone.

Fasting serum grawth hormone was markedly elevated in 2,

slightly elevated in 3, with the other patient demonstrating an

unusually high response to glucogan!propranolol in the 30 minute

specimen. Voluntary weight loss amenorrhea is similar to

anorexia nervosa except for the associated psychiatric a5norm-

alit y.

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The etiology of secondary amenorrhea m a y be multiple

including hyperandrosenic states such as polycystic ovaries, * *

ovarian o r uterine failure, hypopituitarism, hypothalamic

disorders, neurologic disease, o r psychogenic causes.

Cessation of menses fo l lodzg weight loss associated with

anorexia nervosa has been known for many years and the 1

amenorrhea m a y even precede the weight loss. 1-4 ~ o t only i

can involuntary starvation induce secondary amenorrhea but

also voluntary weight-reduction may result in cessation of

the menstrual now. 5-7 Obese women that voluntarily

lose to a desirable or even slightly subnormal weight m a y .

remain amenorrheic for a considerable time after weight

reduction has stabil ized They maypresent with an endocrine

pattern similar to patients with anorexia nervosa without the

associated psychiatric abnormalities. All woml-ra. with second-

a r y amenorrhea need a minimal evaluation to include vaginal

hormonal cytology and cervical mucus for presence of ferning.

If these tes ts indicate hypoestrogenism and a r e confirmed by

failure of withdwwe menses to a progestogen, further endo-

crine evaluation is indicated. 4

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MATERIALS AND *METHODS

During a 2 year in tqv+ 6 nulliparous young wornen, ages

14-21 years, were evaluated for prolonged amenorrhea following 4

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a self-imposed weight loss. P r i o r to their voluntary weight

I reduction, all had regular menses for one o r more years. Two

of these pztients (GOR, LJT) were motivated to lose weight so

that they coula qualify for enlistment in the Air Force.

the 6 used any anorexic drugs to assist them in weight reduction.

None of

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Complete physical examination w a s performed along with vaginal \

horm-onal cytology 2nd ferning of the cervical mucus. Medroxy-

progesterone acetate 10 mg for 5-7 days was given during one or

more courses as an attempt to induce a menstrual period. All

~ 6 were hospitalized and serum collected daily for radioimmuno-

~

a s s a y of FSH and LH. Urine w a s collected on 2 ccnsecutive days

for assay of 17-ketosteroids and 17-hydroxycorticosteroids as a

baseline followed by ACTH 40 I. U. intravenously by infusion.

After a day of r e s t the metyrapone test w a s performed b y giving

750 m g orally every 4 hours for 6 doses. The 24-hour urine

collection -s continued during metyrapone administration and * s

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the following day.

formed in 5 utilizing glucagon 1 m g intramuscularly after pro-

pranolol 100 rhg oran$.

A growth hormone provocative test was per-

* s L-dopa 500 m g orally w a s given to

one patient (Us) instead of the glucagon/propranolol test . Serum

thyroxine (T4 ) and triodothyronine (T3 ) uptake were performed

in all. X - r a y tomography of the sella turcica w a s performed in

3 patients (LJT, CIS, hG). Laparascopy w a s accomplished in

one patient (MAS) during the initial evsluation and in another

(GOR) 3 months after the initial evaluation. 4-

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RESULTS AND FINDINGS

All 6 women were amenorrheic from 4-36 months prior to

the evaluation, had hypoestrogenic vaginal smears, absence of

ferning in the cervical mucus, and failed to have wi'ihdrawclt

menses wher, given one or more courses of a progcstogcn (Table

1). The amenorrhea followed a voluntary weight loss of 13-50

pounds from a self-imposed wcight reduction (Table 2). Weight

loss not only ceased but had also remained stable for 3-24

months prior to evaluation, yet menses had not resumed. There

were 4 patients who were initially obese and lost to a near normal

I I . , .

weight. The other two (EUIAS, CLC) voluntarily lost weight because

of a desire for a thin body image. Their final weight w a s 79% and

06% of normal according to weight standards for females in AFR * %

160-43. This is the A i f Force c Regulation listing standard, min-

imum, and maximum weights for all military personnel.

Serulm FSH w a s within the normal range for all 6 while 2

(MAS, MS) were found to have low serum LH (Table 3). A11

6 were considered to be eGthyroid since either the Tq or T3gptake

w a s normal. T4 w a s slightly elevated in one (CLC) but the T3

uptake ~ d s normal. T3 uptake was slightly elevated in 2 (GQR),

MS); however, the Tq was witSin the norma? range. Urinary

17-hydroxycorticosteroids we c normal in all, increased with

ACTH administration, and responded with at least a 3-fold r i se

during and following the metyrapoae. Urinary 17-ketosteroids

were normal in 4, slightly d e n t e d in 2 (CLC, LLT), and

increased as expected with metyrapone.

Fasting serum growth hormone was markedly elevated in

2 patients (GOR, LJT) and slightly elevated in 3 others (Table 4).

Unfortunately, a laboratory accident precluded radioimniunoas say

of the fasting in one subject (LLT); however, the 30 minute

svecimen w a s markedly e l e n t e d to 39 .2 ng/ml. All women u.n-

dcrgoing the gIucagon/propranoIol provocative test for growtb

hormone had an increase in serum values although one subject * s

(CLC) had a blunted response. The subject (MS) that had the

L-dopa provocative tes t for growth hormone w a s considered to

have an inadequate response although the fasting level w a s

slightly elevated.

Ovarian b i o p s y performed duriag laparoscopy of one

patient (NLAS) at the time of initial evaluation w a s reported as

"numerous primordial follicles. I' X-rays of the sella turcica

were normal in all 3 of those studied (UT, CLC, Ms).

Treatment and Results:

duration of amenorrhea and stabilized weight had a spontan-

The patient (LLr) with the longest

eous resumption of menses before treatment w a s instituted.

The other five women were trcatcd with cyclic estrogen and

progestogen. Ethinyl estradiol 0.02 mg was administered

from the 1 st-25th/month and medroxypragesterone acetate

10 n g w a s given from the 19th-25th/month. Four patients

are sEll receiving this therapy although one has discontinued

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the medication becausz of evidence that normal function was

restored. This patient (COR) had laparoscopy 8 months after

in-tial evaluation with findings of a corpus luteum, confirmed

by o\-arian biopsy. % S .-

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DISCUSSION

Sixxc a.menorrhea is an important syrrrptom of anorexia

nervosa, secondary am-enorrhea in the setting of weight loss

must be carefully evaluated. Our 6 patients did not have

anorexia nervosa since all voluntarily dieted and lost weight,

4 f rom an obese weight to that which was nearly normxl. i

None

were emaciated although 2 were underweight. All 6 desired \

some thinness of body image and 2 were motivated to lose

weight so that they could enlist in the Air Force.

psychiatric investigations were not performed on our yatients

but intensive evaluations have been reported by 0thei.s. 4

Detailed

A normal pituitary-adrenal axis was demonstrated in our

6 patients by normal baseline urinary 17-hydroxycorticosteroid

and 17-ketosteroids with the expected response to metyrapone.

Patients with anorexia nervosa have also been found to have

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normal responses to metopirone ani! ACTH.'. 5* Thyroid

function with normal serum Tf and T3 uptake was fcund in our

patients which has a l so been repoxted in psEen:s with anorexia

nervosa. 1 # 2 * 3

Serum LK and FSH values in our 6 womm were normal

to low indicating normal but acyclic pituitJry function without .

gonadal failure. Patier4ts with anorexia nervosa and weight losrr

* s 4

amenorrhea have been reported to have low to normal LH and

responsiveness to LH-RH was made in our study, but ha? been

reported to be delayed in both patients with anorexia nervosa

and simple weight loss. 7 i

All 6 of our patients had a growth hormone stimulation \

test either to glucagon o r L-dopa. Surprisingly, the 5 women

tested had e levated fasting growth hormone levels. The fasting

serum growth hormone level is usually undetectable (< 0.4 ng/ml)

in our laboratoty for normal women. Patients with anorexia ner-

vosa have elemted fasting growth hormone levels in the range of

OUT patients. 3, 10, 1%

..

T i e finding of elevated fasting serum

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growth hormone levels has not been documented previously

patients k t h voluntary weight loss amenorrhea.

Gonadal function in our patients was evaluated by vag

cytology, examination of the cervical mucus, and administi

I tion of an ora l progestogen. Al l six women had hypocstrog I 1 I vaginal smears which is in agreement with the work of 0th:

'* 2 p 5 p 6*

ierning.

Cerv;,cz.l m u c w was very scant with no eviden

Nane of the 6 had withdrawal bleeding to the progt

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gen. These 3 tests demanstrate lack of sufficient estrogen

production by tSe 0-ries.

Treatment consisted of ethinyl estradiol 0.02 mg fro:

the 1st-25th of each month with a progestin added from the

25th of the month. This resulted in regular withdrawal me

I This dosage of estrogen w a s chosen because not only does .

~

suppress the hypothalamic-pituitary axis but also m a y exei

positive feedback to the pituitary. Some confirmation of th

suppressive effect w a s obbincd b y the finding of a corpus 1

in one patient still receiving this low-dosage estrogen thar.

This patient had not gained weight since the initial evaluatil

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Another of our patients (LLT) resumed spontaneous menses

after 3 years of amenorrhea and 2 years at a stabilized lower i

weight. Further work must be done to determine the complete

l clinical course in patients with voluntary weight loss arnenor-

rhea.

function m a y be established at the new, lower weight.

However, it appears f iat in time reb-rn of normal ovarian

This

supports the work of other authors. 5

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References

Emanuel RW: Endocrine activity in anoreda nervosa. J Clin Endocrinol Metab - 16:80 1-8 16, 1956.

Espinosa-Campos J, Robles C, Gual C, - - et al: Hypothalamic, pituitary and ovarian function assessment in a patient with anorexia cervosa. Fer t i l Steri l -- 25:453-458, 1974.

Frankel RJ, Jenkins JS: Hypothalamic-pituitary functioa in anorexia nervosa. Acta Endocrinol - 78:209-221, 1975.

F r i e s H: Secondary amenorrhea, self-induced weight reduction and anorexia Rervosa. Acta Psychiatr S c a d Suppl - 248, 1974.

Lev-Ran A: Secpncbrpamenorrhea resulting from un- controlled tt-eight-reducihg diets. 1966.

Fer t i l Stcril - 25:437-449,

McArthur J W , Johnson L, Hourihan J, -- et al: Endocrine studies during the refeeding of young women with nutritional amenorrhea and infertility. 1976.

Mayo Clin Proc - 51:607-616,

Vigersky .iiA, Loriaun DL, Andersen AE, -- et al: aelayed pituitary hormone response to L R F and TRF in patients

associated with simple weight loss. Metab - 43:8?3-900, 1974.

Holmberg NG, Nylander I: Weight loss in seccndary amenorrhea. Acta Obstet Gynecol Scand - 50241-246, 1971.

with anorexia nervosa and ~ t h secondary amenorrhea 4- J Clin Endocrinol

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Warren MP, Vande Wiele RL: Clinical and metabolic features of anorexia nervosa. Am J Obstet Gpecol - 117: 435-449, 1973.

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11.

12.

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Sherman Bh4, Halmi KA, Zamudio R: I,H and FSH response to gonadotropin-releasing horl?rone in anorexia nervosa: effect of nutritional re'habilitation. J Clin Endocrinol Metab - 4i:i35-i4t , 1975.

Warren MP, Jeweleuicz R, Dyrenfurth I, -- et al: The signi- ficance of weight loss in the evaluation of pituitary response to Lfi-RH in women with secondary amenorrhea. Endocrinol Metab - 40:601-611, 1975.

J Clin

Landon J, Greenwood FC, Stamp TCB, -- et al: The plasma sugar, free f a t t y acid, cortisol, and growth hormone response to insulin, and the comparison of this procedure with other tesfs 'bf pftuitary and adrenal function. 11. In patients with hypothaBmic or pituitary dysfunction or anor- exia nervosa. J Clin Invest - 45:437-449, 1966.

Address requests for reprints to:

R. Don Gambrell, Jr., Colonel, USAF, MC Department of Obstetrics aqdGynecology Wilford Hall USAF Medical Center Lackland AFR, Texas 78236 4-

Table 1. CLINICAL CHARACTERISTICS

Duration& 3 Cervical Response to atient Age Arnenorhea c Vaginal Smear Mucus P rog e stogel:

MAS 14 11 Months Hypoestrogenic N o Fern No Menses

18 4 Months H ypoest rogenic No Fern No Menses

WT 18 4 Months Hypoestrogenic No Fern No M a s e a

3LC 19 8 Months Hypoestrogenic No Fern No Menses

20 36 Months H ypaest rogenic No Fern No'Menee B

Ms 21 13 Months H ypoe strogenic No Fern N o Mensee

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