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Post-pill and pill-related amenorrhea-galactorrhea
Post-pill and pill-related amenorrhea-galactorrhea RICHARD
D.
GAMBRELL,
JR.,
LIEUTENANT
COLONEL,
USAF(MC)* ROBERT
B.
VIRENDRA Augusta,
GREENBLATT, B.
MAHESH,
M.D. PH.D.,
D.PHIL.
Georgia
Amenorrhea and galactorrhea have been encountered in 10 women following usage of the contraceptive pill. Five had @e-existing amenorrhea, but in 5 the amenorrhea had its onset upon cessation of contraceptive therapy. In 3, the galactorrhea started while taking the pill; it began after cessation of therapy in three, while the others were unaware of the galactorrhea until the breasts were compressed during examination. Post-pill amenorrhea-galactorrhea simulates the Chiari-Frommel syndrome. In both, the influence of prolonged estrogens and progestogensendogenous in one, exogenous in the other-disrupts the hypothalamic-pituitary axis, resulting in amenorrhea and galactorrhea. Serial serum gonadotropins for radioimmunoassays for follicle-stimulating hormone and luteinizing hormone were performed on 5 patients for 21 days prior to, during, and following clomiphene therapy, and urine assays for estrogen and 17-ketosteroid fractions were also done. Prior to clomiphene therapy, mean serum gonadotropins were generally lower than those found in our laboratory in the ovulatory cycle. Therapy with clomiphene, followed by human chorionic gonadotropin, is the treatment of choice, although the response is not predictable. Seven of 9 patients have ovulated, resulting in 3 conceptions.
amenorrhea and galactorrhea following parturition as a distinct entity. Some decades later, Frommellb again brought this condition to light, and it is now known as the Chiari-Frommel syndrome. Then, in 1932, Ahumada and de1 Castillo? pointed out that amenorrhea-galactorrhea could exist in nulliparous women. Attention was again in 1953 focused on the occurrence of nonpuerperal amenorrhea-galactorrhea by Argonz and de1 Castillo.3 In 1954, Forbes and associates” observed similar cases but noted a high incidence of pituitary tumors in their series. Arbitrarily, the association of a pituitary tumor with amenorrhea-galactorrhea is designated as the Forbes-Albright syndrome. In 1966, Shearman’ reported amenorrheagalactorrhea following the administration of oral contraceptives. To date, a total of 41 cases of “post-pill” amenorrhea-galactorrhea have appeared in the literature.5-12 This study of 10 women with amenorrhea-galactorrhea following usage of the contraceptive
HIP P oc RATE s made the astute observation, “If a woman who is not with child, nor has brought forth, have milk, her menses are obstructed.” Thus, he was the first to record the syndrome of amenorrhea and galactorrhea existing simultaneously. In 1855, ChiarP recognized the persistent
From the Department of Endocrinology, Medical College of Georgia. Support furnished in part by Research Grant No. AM-04429-10 from the National Institute of Arthritis and Metabolic Diseases, United States Public Health Service, and in part by General Research Support Grant No. 5-501RRO-5365-10, United States Public Health Service. Presented at the Thirty-third Annual Meeting of the South Atlantic Association of Obstetricians and Gynecologists, Atlanta, Georgia, February 7-10, 1971. The opinions or assertions contained herein are those of the authors and are not to be construed as oficial or reflecting the views of the Department of Defense. *United States Fellowship.
Air Force
Research
838
Post-pill
pill attempts to define the deficiencies the treatment of this syndrome. Materials
and
in and
methods
Ten patients with amenorrhea and galactorrhea following oral contraceptive therapy were studied; 9 were hospitalized for an endocrine survey.* Serum gonadotropins and basal body temperature prior to, durin,?, and following clomiphene therapy were obtained daily in the 5 patients who were able to stay in the hospital for a period of 21 or more days. In addition, urinary steroid assays, vaginal smears, and cervical mucus studies were obtained frequently. Endometrial biopsies were taken prior to and after treatment. Subsequent to this initial hospital study, therapy was continued, and various parameters of response were utilized to indicate ovulation. Each patient had an infertility investigation prior to therapy, consisting of husband’s evaluation, postcoital cervical mucus studies for spermatozoa, and hysterosalpingogram, in addition to the studies detailed in this report. Fractionation and individual estimation of various urinary steroids were done by the method of Mahesh and colleagues’38; urinary estrogen determinations were performed by the method described by Mahesh I::b Findings
and
results Menstrual history. Patients into two groups based on the orrhea. Group A patients are “post-pill” because amenorrhea set after therapy with oral
were divided onset of amendesignated as had its oncontraceptives.
*Materials for radioimmunoassays of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were generously supplied by the National Pituitary Agency and National Institute of the Endocrinology Study Section, Health: (1) Human follicle-stimulating hormone, LER 869-2, 1 mg. = 2,782 I.U. of FSH and 92 I.U. of LH; (2) Human luteinizing hormone, LER 960, 1 mg. = 923 I.U. of LH and 1.9 I.U. of FSH; (3) Human pituitary FSH antiserum (rabbit) ; (4) Human chorionic gonadotropin antiserum (rabbit); (5) Human pituitary extract reference preparation, LER 907, 1 mg. = 20 I.U. of FSH and 48 I.U. of LH. These techniaues are based on the radioimmunoassay principle. with the use of specific doubleantibody systems. We are indebted to H. F. L. Scholer for assistance in the radioimmunoassay of serum gonadotropins. The cis and tram isomers of clomiphene citrate were supplied by the Wm. S. Merrell Co., Cincinnati, Ohio.
and
pill-related
amenorrhea-galactorrhea
839
Group B patients are designated as “pillrelated” because oral contraceptives wcrc administered in the management of preexisting amenorrhea. In both groups of patients, the galactorrhea had its onset either during therapy or after discontinuation of therapy, and all were amenorrheic foilowing cessation of the pill. Five of the 10 patients had previously conceived, and all but one of the nulligravidas had regular cycles indicating a high incidence of previous ovulatory cycles in the entire group (Table 1).
Type and duration of oral contraceptives. At least 4 different pills or dosages were involved, failing to implicate a specific compound. The combined pill was employed in 6 patients, the sequential in two: and unknown, in the other two (Table II Duration of therapy varied from 6 months to 4 years, with half being on therapy lor two years or less. Duration of amenorrhea-galactorrhea. Of the 10 patients under study, 6 had “postpill” amenorrhea of 4 or more years (Table I). Galactorrhea was noted during oral rontraceptive therapy in 3 patients and following cessation of therapy in 3: and in the remainder galactorrhea was not dixovered until the breasts were compressed durin,? examination.
Serum gonadotropins and other findings. Radioimmunoassay of serum gonadotropins was performed in 8 patients, and results were normal to low. Serum FSH was within the range found in our laboratory for the follicular phase of the ovulatory cycle (Table II), though 3 patients (D. S.? C;. P. and D. McE.) had values considerably lower than our mean laboratory value (6.:i m1.U. per milliliter of serum). Mean serum LH values in the 6 patients with serial determinations were all lower than the mean serum LH values for our laboratory (6.5 m1.U. per milliliter). Vaginal smears ransed from moderately hypoestrogenic to almost castrate in all patients, and endometrial biopsies were atrophic or moderately hypoplastic (Table II). Urinary estrogens were low in 3 of the 5 studied. X-ray of the sella turcica was normal, as were thyroid studies and estimation
840
Gambrell,
Greenblatt,
Table I. Clinical
and
history
Mahesh
of post-pill
and pill-related
amenorrhea-galactorrhea
Patient Post-pill G. C.
13
28-42
Norethindrone, 2 mg., and mestranol, 0.1 mg.
V. G.
26
0
11
28
Norethindrone, 2 mg., and mestranol, 0.1 mg.
15
48
52”
D.
S.
23
0
13
Irregular
Norethindrone, 2 mg., and mestranol, 0.1 mg.
12
7
7
L. T.
26
1
11
28
36
48
48
c.
s.
29
1
12
30
“Combined”
8
51
Pill-related G. P.
34
Abl
11
Amenorrheat
Norethynodrel, 2.5 mg., and mestranol, 0.1 m.5.
42
72
P. w
39
0
12
Amenorrheag
30
30
D. McE.
27
0
12
Amenorrheat
Chlormadinone, 2 mg., and mestranol, 0.08 w
48
48
S. H.
32
1
14
Amenorrheaz
Norethynodrel, 5 mg., and mestranol, 0.075 mg.
6
54
t
L.
26
0
14%
Amenorrheat
Chlormadinone, 2 mg., and mestranol, 0.08
24
36
t
B.
*Galactorrhea +Galactorrhea $Had
fairly
of urinary steroids.
onset
while
detected regular
taking on
cycles
?
t 72
t 60”
pills.
initial
physical
before
onset
17-ketosteroids
?
and
examination. of
amenorrhea.
17-ketogenic
Changes in serum gonadotropins and various urinary steroids during and following clomiphene therapy in the 5 patients hospitalized for 21 days. In Patient G. C. the basal body temperature did not change following treatment for 6 days with cisclomiphene, 25 mg. (Fig. 1) . Serum gonadotropins showed little responsiveness to therapy, FSH remaining rather tonic. Serum
LH was low prior to therapy; some sporadic spikes occurred afterward. Urinary estrogens remained low during and following treatment. Both the 17-ketosteroids and 17-ketogenie steroids were within the range of normal with only a slight increase in 17-ketosteroids following therapy. Treatment in the second cycle consisted of trans-clomiphene, 20 mg. for 10 days followed by human chorionic gonadotropin (HCG) 4 days later without any evidence of ovulation. In the
\ olume kumber
110 6
Post-pill
Table II. Laboratory, cytology, amenorrhea-galactorrhea
and
pill-related
and tissue studies of post-pill
amenorrhea-galactorrheo
841
and pill-related
Patient Normal
follicular
values
6.3(51)*
Post-pill G. c. V. G. D. S. L. T. c. s.
2+ 2+ 3+ 3+ 2+
Hypoplasia Hypoplasia Hypoplasia Hypoplasia
5.7(5)* 5.9(6) 4.9(6) 9.7(l) 6.4( 3)
Pill-related G. P. P. w. D. McE. S. H. L. B. -
I+ 3+ 2+ 2+ 2-k
Atrophic Atrophic Hypoplasia Atrophic
“Number
of determinations
6.5(48)*
3.2(5)” 2.3(6) 5.7(6) 11.0(l) 5.5(3)
9.3(z)* 10.8( 2) 6.7(2)
3.8(6)
2.1(6)
4.3(6)
4.5;)
6.8(2) 8.6( 2) 1?.1(2)
8.0;)
11.671)
13.0;)
9.1(?)* 8.8(?) 7.4(“) 6.5(2)
fi.4(‘i1” 9.-l(2) 16.!(2)
6.3(2) l&5(2) 11.1(Z)
i.!.T(:j ‘--~6.1(3)
5.572)
-I__
6.6(l)
--...-.---.
.~ _ .---
in parentheses.
third treatment cycle, this patient had an ovulatory response to cis-clomiphene (50 mg. for 10 days) and HCG (5,000 I.U. 5 days later), as judged by basal body temperature. There was nothing indicative of an ovulatory response in Patient V. G. treated with trans-clomiphene, 100 mg., for 5 days (Fig. 2). There was no posttreatment change in the basal temperature graph, and the endometrium remained hypoplastic on biopsy. Serum FSH continued with sporadic spikes and serum LH remained low. There was no change in any of the urinary steroids. This patient has been treated with clomiphene and both its isomers for several cycles without obtaining an ovulatory response. Following cis-clomiphene therapy in Patient D. S., there was some slight rise in both serum FSH and LH (Fig. 3). Urinary steroids were within the range of normal and did not change. Since the patient had no rise in basal body temperature following 10 mg. of cis-clomiphene for 5 days, HCG. 5.000 I.U., was given IO days afterward. A short sustained rise in temperature was noted 7 days later, lasting only 6 days. Treatment was sufficient to induce menses in this amenorrheic patient but the endometrial biopsy was proliferative. Subsequent treatment with cis-clomiphene, 10 mg., for 5
days alone resulted in 3 presumptive ovulatory cycles, because of the biphasic temperature curves; however, she has not as yet conceived. The response of serum gonadotropins to therapy with 100 mg. of cis-clomiphenc for 5 days is of significance in Patient G. P. (Fig. 4). Serum FSH increased slightly following therapy to levels found in the follicular phase of the normal ovulatory cycle with a mid-cycle FSH surge similar to that found in ovulatory cycles. However, serum LH remained very low and quite tonic. Urinary estrogens and fractionation of the other urinary steroids indicated little change. Prior to and since this study cycle, this patient has not shown any indication of ovulation with multiple treatment cycles with clomiphene and both its isomers, with or without HCG. However, she has ovulated according to biphasic temperature, cervical mucus, vaginal cytology, and endometrial biopsy in two out of two cycles treated with human menopausal gonadotropins, 16 to 18 vials in 10 days, and HCG, 5,000 T.U., though she did not conceive. In Patient D. MC&, there was a~uiincrease in serum FSH during therapy with 20 mg. of cis-clomiphene for 5 days but LH remained quite low and rather tonic (Fig. 5). Urinary estrogens assayed at nearly double
842
Gambrell,
Greenblatt,
and
Mahesh
POST-PILL AmrfwrhwGolactorrhra
POST-PILL Amenorrhea-Goloctorrhea
n
GC Ape 24
tE r E”
C 17.Ketogeaic Steroids
50.
o-,.,,,~..,...,................, DAYS
Fig. 1. Anovulatory response to cis-clomiphene in a patient with amenorrhea-galactorrhea secondary to oral contraceptive therapy. Note sporadic increases of LH during and following clomiphene therapy without change in FSH (E-, hypoplasia; E, proliferative).
values while on therapy with a peak similar to the preovulatory one observed in the normal ovulatory cycle, occurring on the thirteenth and fourteenth day after treatment was initiated. There was no significant change in 17-ketosteroids or 17-ketogenic steroids. Since this patient had no indication of ovulation by the fifteenth treatment day, either by basal temperatures, vaginal smears, or cervical mucus, HCG, 5,000 I.U., was administered. On biopsy, the endometrium had converted from hypoplasia to proliferative on this day. This patient conceived during this treatment cycle, most probably the first or second day following HCG administration, though the basal tem-
OIYS
Fig. 2. Anovulatory response to trans-clomiphene in a patient who noted galactorrhea during oral contraceptive therapy. Amenorrhea followed cessation of oral contraceptive therapy with persistence of galactorrhea. Note that serum LH remained low following therapy with a mean value of 2.8 m1.U. (normal follicular levels, 6.5 m1.U.) while serum FSH stays within the range of normal with a mean value of 6.1 m1.U. (normal, 6.3 m1.U.) (E-, hypoplasia) .
perature graph is not available to aid in detecting the day of ovulation. Labor was induced by oxytocin infusion March 14, 1971, with delivery of a normal 9 pound, 4 ounce female. Treatment and results. Of the 10 patients, 9 presented for infertility and one, because of lactation. They were treated with various regimens to induce ovulation (Table III). The difficulty in inducing ovulation in these patients is well demonstrated by the multiplicity of regimens and the frequency of failure. To date, all 5 of the pill-related
Volumr Nulnhcr
Post-pill
Il(l h
and
pill-related
t ‘t”i”Qt
843
PILL-RELATED Amenorrhro-Galactorrhro
POST-PILL Amrnorrhea-G‘~loctorrhM
cis-Clomid
amenorrhea-galactorrheo
HCG
5.000 1
IU
DAYS
Fig. 3. Anovulatory response to cis-clomiphene in a patient that became amenorrheic with galactorrhea following one year of oral contraceptives. Note the increase in serum LH during therapy and FSH following therapy. Seven days after HCG, basal temperature rose for 6 days only and biopsy of endometrium at onset of menses was proliferative (E-, hypoplasia; E, proliferative).
amenorrhea-galactorrhea patients have ovulated and 3 have conceived. Only 2 of the 4 post-pill patients have ovulated, but neither has conceived. Comment
After a decade of ever-increasing utilization of oral contraceptives, in which the decrease in side effects has paralleled the lowering of dosage, more and more attention has been drawn to a variety of complications. Post-pill amenorrhea of varying duration, first reported in 1966,5?I4 has been confirmed by several authors. 6a~7l * This condition is rare, and, if left untreated, many patients will spontaneously menstruate. Larsson-CohnI studied the length of the
DAYS
Fig. 4. Anovulatory
response to cis-clomiphene in an amenorrheic patient who developed galactorrhea after oral contraceptive therapy. Note the increase in serum FSH following clomiphene with a mid-cycle FSH surge similar to that found in ovulatory cycles while LH remained quite low and tonic.
first 3 menstrual cycles after combined pill therapy in 516 women. Only 4 of these women had amenorrhea for 6 or more months but 3 had irregular mensesbefore therapy. Furthermore, Rice-Wray and her associatesl@reported “the return of ovulatory function appears to be equally prompt whether contraception was used for 1 to 4 or 5 to 6)$ years.” In their study of 163 women, more than 75 per cent ovulated in the first posttreatment cycle and 98 per cent ovulated within the first 3 cycles, In our
844
Gambrell,
Greenblatt,
and
Mahesh Amer.
PILL-RELATED Amsnorrhca-GalactorrhW D.McE Age: 27
Sosol Body Temperature
EDC 20 Fcb 71
ssss
Y E
97-J Ii 4 10.0 ‘0 -c 2" 0I
;
:\
~:
F
Implontotion Spotting
I
‘k/t)
‘A
‘+
50
:
0
z 2 +IE
,.
-1
FSH---
LH -
I
I:
n
n z , 0.0 : P 5.0 1 OJ
,o.or 0’ N
17- Keto,laoidr
dll n
J-
r-
n 1
5.0.
I7-Kotogenic
Steroids
P on-n.:.,,~:,,.:~:.:~I 9 13 MAY
17
1970
2,
25
29
I 3 5 JUNE
Fig. 5. Response to cis-clomiphene in an amenorrheic patient developing galactorrhea while taking sequential contraceptives. Note the increase in serum FSH during the therapy while LH remained low and rather tonic. Urinary estrogens increased during clomiphene administration with a peak similar to that observed preovulatory, the thirteenth and fourteenth days after initiation of therapy. HCG, administered 10 days after clomiphene, was sufficient to induce ovulation in that the patient conceived in this cycle and was delivered March 14, 1971 (E-, hypoplasia; E, proliferative) .
July 15, 1971 J. Obstet. Gpncr.
own experience with several thousand patients taking oral contraceptives for more than 4 years, post-pill amenorrhea has indeed been rare. More important, from the standpoint of prognosis and therapy, than post-pill amenorrhea is amenorrhea coexistent with galactorrhea. Three of our patients noticed the onset of galactorrhea while taking birth control pills; 4 were unaware of the presence of milk until it was demonstrated on the initial breast examination. Friedman and Goldfie+ reported that 3 of their 9 patients with galactorrhea noted breast secretions during contraceptive therapy, but 4 were not aware of lactation until examined for it. It is apparent that galactorrhea is far more prevalent than previously supposed, and the breasts of each new patient should be compressed, especially those with amenorrhea. Since 5 of our 10 patients had previously been pregnant, the finding of galactorrhea in nulliparous women, with or without amenorrhea, is significant. Post-pill and pill-related amenorrheagalactorrhea simulates the isolated pituitary syndrome, characteristic of the Chiari-Fromme1 syndrome. In both, the influence of prolonged estrogens and progesterone-endogenous in one, exogenously administered in the other-disrupts the hypothalamic-pituitary axis, resulting in amenorrhea and galactorrhea. The length of suppression of the hypothalamus with these potent steroids need not be excessive, in that 5 of our 10 patients were receiving therapy for 2 years or less, 3 of these less than one year. In the 10 patients with post-pill amenorrhea-galactorrhea reported by Shearman and Turtle,l” the duration of contraceptive therapy was less than 2 years in 7 of them. It appears that patients with prior menstrual irregularities are more prone to develop post-pill amenorrhea-galactorrhea. Half of our patients had amenorrhea (Group B) and had been treated with oral contraceptives to induce menstrual periods before consulting us. In addition, 2 of our 5 postpill patients (Group A) had menstrual irregularities prior to contraceptive therapy,
Post-pill
Table
III.
Treatment
and
pill-related
amenorrhea-galactorrhea
845
and results _...--. -_. -.
Patient
Clomiphene/
Post-pill G. C. V. G. D. S. L. ‘I-. c. s.
0
Pill-related G. P. P. w. D. McE. S. H. I,. B. -__
0 Z= anovulation;
Transclomiphene/
and HCG
and HCG
Cisclomiphene/
0 Not
HMG
and HCG
+
0 0
and HCG
(1 -i-
0
treated as yet
0
0
0 n 0 + = ovulation.
0 0
0
n n
0
4 f -1-X
il
0
i*
+* HMG
=
human
menopausal
yonadotropill.
____
~_- . . .._
.~ .-
“Conwived.
though 3 did have previously regular cycles. Friedman and GoldfienGa and Halbert and Christian? noted menstrual irregularities in a high percentage of their patients prior to pill therapy. However, Shearman and TurtWo found only one in their series that had irregular cycles. It would seem prudent, therefore, to utilize some other therapy rather than oral contraceptives to regulate the irregular menstrual cycle. No consistent pattern was found in serum gonadotropins, though there is a tendency for both serum FSH and LH to be slightly lower than mean values in our laboratory for the follicular phase of the normal ovulatory cycle. All 6 of the patients with serial determinations had mean serum LH values below normal and 4 (Figs. 1, 2, 4, 5) had rather low, tonic serial serum LH patterns. The serum gonadotropin pattern in these anovulatory women appears to be different from that in the Stein-Leventhal syndrome where FSH rather than LH is found to be consistently low. These results are not surprising since in the isolated pituitary syndrome low serum gonadotropins and elevated prolactin would be expected. Urinary estrogens were low in 3 out of our 5 patients studied, results which are in agreement with those of Shearman and Turtle.l” Vaginal smears in our patients were generally hypoestrogenic as were endometrial biopsies in that 3 out of 8 were atropic
while the remainder showed hypoplasia, a finding also observed by Halbert and Christian.7 In patients that generally ovulate with clomiphene, there is a small but significant rise in serum FSH and LH during administration of the drug, followed by an ovulatory surge of both FSH and LH 10 to 15 days from the start of treatment. One patient (Fig. 3) had such a rise of both serum FSH and LH during therapy, but no surge was observed during the period of observation. Even though HCG was given 10 days after clomiphene, there was no evidence of ovulation in this cycle. Subsequent treatment with this agent alone in the next 3 cycles resulted in 3 presumptive ovulatory cycles as evidenced by biphasic temperature curves. Another patient (Fig. 4) had a rise in serum FSH during treatment followed by a midcycle surge of FSH similar to that seen in ovulatory cycles, but serum LH was low and continued quite tonic. This patient did not receive HCG, and there was no evidence of ovulation by any of the criteria utiked. The patient who conceived during the study cycle (Fig. 5) had a rise in serum FSH during clomiphene administration which returned to low levels after discontinuation of the drug. Serum LH remained low and tonic, and no surge of either FSH or LH was observed during the remaining serial serum gonadotropin collection, However,
846
Gambrell,
Greenblatt,
and Mahesh
HCG, administered 10 days after clomiphene, was sufficient to induce ovulation leading to conception. A survey of the data presented in Table III shows that whereas clomiphene alone did not induce ovulation in 6 out of 7 patients ovulations were obtained in 4 out of 6 patients, resulting in 2 conceptions, when HCG treatment was added. The possibility that the LH-like activity in HCG contributed to these ovulations in patients who had rather low tonic LH levels may be considered. The response to the therapy of infertility in patients presenting with pill-related amenorrhea-galactorrhea varies from poor to moderate.‘Op I1 Of the 19 patients with
post-pill amenorrhea (9 with galactorrhea j, Friedman and Goldfien@ obtained conceptions in 8 of the 15 that were treated. They did not separate their amenorrhea-galactorrhea patients from the simpler post-pill amenorrhea. In our own series, only 3 of 9 patients desiring pregnancy have conceived to date though ovulation presumably has been induced in 7 of the 9. Only one patient had ovulated with clomiphene alone, 4 required clomiphene and HCG, and 2 needed menopausal gonadotropins and HCG. Our present routine is to use clomiphene first, or one of its isomers, adding HCG if there is no response. In those patients who do not respond to either of these, menopausal gonadotropins and HCG are given.
REFERENCES
la. Chiari, J., Braun, Cl., and Spaeth, J.: In Speert, H., editor: Obstetric and Gynecologic Milestones, New York, 1958, The Macmillan Company.. lb. Frommel, J. T.: In Speert, H., editor: Obstetric and Gynecologic Milestones, New York, 1958. The Macmillan Comnanv. 2. Ahumada, J. C., and de1 C&lo, E. B.: Bol. Sot. Obstet. Ginec. 11: 64, 1932. 3. Argonz, J., and de1 Castillo, E. B.: J. Clin. Endocr. 13: 79. 1953. 4. Forbes, A. P., ‘Henneman, P. H., Griswold, G. C., and Albright, F.: J. Clin. Endocr. 14: 265, 1954. 5. She&man, R. P.: Lancet 2: 1110, 1966. 6a. Friedman. S.. and Goldfien. A.: T. A. M. A. 210: 1888, 1969. 6b. Friedman, S., and Goldfien, A.: AMER. J. OIISTET. GYNEC. 104: 846, 1969. 7. Halbert, D. R., and Christian, C. D.: Obstet. Gynec. 34: 161, 1969. I
Y
Discussion
DR. LEO J. DUNN, Richmond, Virginia (By invitation). The importance of the hypothalamic centers in the regulation of pituitary function has been recognized since the early 1930’s. The identification of specific centers in the hypothalamus controlling specific factors has been a further advance in our knowledge. More recently, isolation, purification, structural analysis, and even syntheses of releasing factors promise new experimental tools and therapeutic approaches to problems of dysfunction in this area.
8. MacLeod. S. C.. Parker. A. S.. and Perlin. I. A.: AMER. J. O~STET. G~NEC. IO6: 359, 1970. 9. Nyirjesy, I.: Obstet. Gynec. 32: 52, 1968. 10. Shearman, R. P., and Turtle, J. R.: AMER. J. OBSTET. GYNEC. 106: 818, 1970. 11. Arrata, W. S. M.: Ob.Gyn. News 5: November 1, 1970. 12. Greenblatt, R. B., Scholer, H. F. L., and Mahesh, V. B.: Proc. 52nd Meet. Endocrine Sot. June, 1970. 13a. Mahesh, V. B., Greenblatt, R. B., Aydax, C. K., Roy, S., Puebla, R. A., and Ellegood, J. 0.: J. Clin. Endocr. 24: 1283, 1964. 13b. Mahesh, V. B.: Steroids 3: 647, 1964. 14. Whitelaw, M. J., Nola, V. F., and Kalman, C. F.: T. A. M. A. 195: 780. 1966. 15. Larssoi-Cohn, U.: Acta ‘Obstet. Gynec. Stand. 48: 416, 1969. 16. Rice-Wray, E., Correu, S., Gorodovsky, J., Esquivel, J., and Goldzieher, J. W.: Fertil. Steril. 18: 212, 1967. Early experimental work in the hypothalamus demonstrated that creation of destructive lesions in particular areas would lead to specific functional changes. It was further recognized that similar functional derangements could also be created by the administration of a variety of drugs seemingly unrelated to the endocrine system. These discoveries have shown that some dysfunctions of the pituitary can be attributed to abnormalities of hypothalamic control and that these malfunctions may come from organic
Post-pill
lesions such as the tumors associated with the Forbes-Albright syndrome, nonhormonal chemical influences as with the phenothiazines, emotional disturbances, or intrinsic malfunctions or hormonal influences as illustrated in the precedinf paper. The authors have presented two apparently different groups of patients. One group had a primary or spontaneous menstrual disturbance perhaps worsened by exposure to oral contracvptivcss; the other had a secondary onset menstlual disorder possibly induced by oral contraceptives. Such spontaneous or primary disorders may be analagous to the Ahumada-de1 (Lstillo syndrome whereas the secondary type m,ty be analagous to the Chiari-Frommel syndt omr. The finding of breast secretion upon careful examination of a parous woman is not necessarily a pathologic finding as demonstrated by Friedman and Goldfien.1 A higher association with pathology appears to exist when: (1) breast srscretion is found in a nulliparous female with no drug exposure, and (2) a symptomatic flow of milk (galactorrhea) is found in any woman M ho has not recently breast fed. The inclusion by most authors of cases of alnenorrhea with those of amenorrhea and galitctorrhea seem to reflect the opinion that they rc,present varying manifestations of the same underlying pathology when studies of thyroid, adrenal function, etc., are normal. Further ssparation of these patients may be possible with progress in our understanding of the hypothalamic factors and their availability for clinical use. For the present time it might be useful to cl,nsitler as a separate group the previously mentioned patients who have more obvious pathologic lactation and galactorrhea. The effects of lactation on hypothalamic and gonadal function are as yet unclear. We need to remember the work of torbrs and co-workers,* and Keettel and BradI>ury,,! suggesting ovarian refractoriness to gonatlotropins in the presence of lactation as a possible explanation for some treatment failures. The issue remains as to whether or not the use of oral contraceptives is causally related to the reported cases of amenorrhea or amenorrheagalactorrhea. The marked effect of sex steroids on the pituitary have been known since the studies of Greep and Jones.4 in 1950. Patients I\rith previously normal menstrual cycles and normal fertility have developed the syndrome. One would, therefore, have to accept the hypoth-
and
pill-related
amenorrhea-galactorrhea
847
esis that a very small group of otherwise normal females will develop a serious menstrual aberration following the use of oral contraceptives. Perhaps of greater importance is the awareness that patients with pre-existing menstrual abnormalities, while representing only a small percentage of oral contraceptive users, constitute a large percentage of the post-pill amenorrhea cas(‘s. In the report of Halbert and Christian,5 25 of 35 cases had a preceding menstrual abnormality and 7 of these were given oral contraceptives for the purpose of regulating menses. The importance of careful evaluation of menstrual discbrtlcrs rather than the casual treatment with oral ho+ mones should bc emphasized. The authors of this paper have not only reviewed their experience with this interesting syndrome but have shown the evaluation nt*c rssary to rule out other endocrinopathies, brain tumm,, and coincidental health problems before establishing a diagnosis and proceeding with therapy. I would like to ask Dr. Greenhlatt to comment on the relationship between the low rstrogcn activity in his patient groups and its c*ffrbct on the results with therapy. REFERENCES
1. Friedman,
S., and Goldfien, A.: AMER. J. 104: 846, 1969. Forbes, A. P.. Henneman, P. H., Griswold. G. C., and Albriqht, F.: J. Clin. Endncr. 14: 265, 1954. Keettel, W. C., and Bradbury, J. T.: +%MER. J. 0Bs.rE.r. GYNEC. 82: 99.5, 1961. Greep, R. O., and Jones, C.: Recent Progr. Hormone Res. 5: 197, 1950. Halbert, D. R., and Christian, C. D.: Obstet. Gynec. 34: 161, 1969. OBSTET.
2. 3. 4. 5.
GYNEC:.
DK. LUTHER M. TALBERT, Chapel Hill, North Carolina. Oral contraceptive compounds have now been generally available for ten years, and their side effects and the complications oi’ theil use ;ire rapidly being delineated. An irlcrea.Ged incidence of thromboembolic disease is wtl11 documented, and the inc.reased annual death rate in young women taking oral contraceptives is probably about 1.5 to 3jlO0,OOO w0men.l Some reports have suggested an association with cerebral vascular throml)oses, hut a relationship is unproved.2 Spellacy” and others have shown striking alterations in glucose metabolism including elevation of plasma glucose, growth hormoncx, and insulin, giving rise to as yet undocumented fears of permanent changes after long-trrm therapv.
848
Gambrell,
Greenblatt,
and
Mahesh
Protein-bound iodine and BEI are increased because of the rise in binding proteins. Pill amenorrhea is probably more common than the few reports in the literature suggest. Although Dr. Greenblatt’s patients with galactorrhea and amenorrhea responded poorly to clomiphene alone, Friedman and Goldfien4 state that the response to therapy in this group is the same as those with amenorrhea alone. Both reports, however, are based on small groups of patients. We have studied 10 patients with post-pill amenorrhea of over one year’ duration during the past 5 years, 3 of whom have had associated galactorrhea. Two of these patients spontaneously resumed apparently ovulatory cycles as shown by temperature charts and endometrial biopsies. Duration of amenorrhea in these 2 patients was 16 and 25 months. The third patient does not desire a pregnancy at the present time and has not been treated. Only 2 of our patients with post-pill amcnorrhea had pre-existing menstrual irregularities. Endocrine studies including 17 ketosteroids, 17 hydroxycorticosteroids, urinary gonadotropins, and thyroid function tests were consistently normal, but 6 of the 10 patients had evidence of estrogen deficiency on vaginal smears. Dr. Greenblatt’s finding of decreased serum LH levels offers an explanation for the high incidence of estrogen deficiency reported in these patients. I would like to ask Dr. Greenblatt for his recommendation for therapy in the patient with more than one year of pill-related amenorrhea but who does not desire a pregnancy. Should she be treated, and, if so, how far would the author progress in the treatment schedule outlined in his paper?
REFERENCES
1. Hellman, L. M.: Second Report of the Advisory Committee on Obstetrics and Gynecology, Food and Drug Administration, August 1, 1969. 2. Cole, M.: Arch. Intern. Med. 120: 551, 1967. 3. Spellacy, W. N.: AMER. J. OBSTET. GYNEC. 104: 448, 1969. 4. Friedman, S., and Goldfien, A.: J. A. M. A. 210: 1888, 1969. DR. GREENBLATT (Closing). In reply to Dr. Dunn’s query, let me say that in our experience the patient with low endogenous estrogen production is, somewhat handicapped in the ultimate response to clomiphene. However, we have had several instances where the individual had castrate smears and atrophic endometrium, particularly in those with Chiari-Frommel syndrome, who responded satisfactorily, ultimately conceiving and carrying to term. Dr. Talbert again brings to our attention the metabolic disturbances that occur during longterm ingestion of the pill. Allow me to emphasize the fact that despite elevated PBI and T4 findings to my knowledge no patient has ever exhibited evidence of thyrotoxicosis. Decreased tolerance for carbohydrates has been documented, but only in a rare case has this; imbalance persisted and such an occurrence may merely represent the unmasking of a latent diabetic diathesis. As far as therapy for the post-pill amenorrheic patient who does not desire conception, we feel that the simple administration of an estrogenprogestogen compound for 5 days per month is sufficient to induce withdrawal periods. In this way, the anxieties associated with the amenorrhea may be eliminated.
D.
GAMBRELL,
JR.,
LIEUTENANT
COLONEL,
USAF(MC)* ROBERT
B.
VIRENDRA Augusta,
GREENBLATT, B.
MAHESH,
M.D. PH.D.,
D.PHIL.
Georgia
Amenorrhea and galactorrhea have been encountered in 10 women following usage of the contraceptive pill. Five had @e-existing amenorrhea, but in 5 the amenorrhea had its onset upon cessation of contraceptive therapy. In 3, the galactorrhea started while taking the pill; it began after cessation of therapy in three, while the others were unaware of the galactorrhea until the breasts were compressed during examination. Post-pill amenorrhea-galactorrhea simulates the Chiari-Frommel syndrome. In both, the influence of prolonged estrogens and progestogensendogenous in one, exogenous in the other-disrupts the hypothalamic-pituitary axis, resulting in amenorrhea and galactorrhea. Serial serum gonadotropins for radioimmunoassays for follicle-stimulating hormone and luteinizing hormone were performed on 5 patients for 21 days prior to, during, and following clomiphene therapy, and urine assays for estrogen and 17-ketosteroid fractions were also done. Prior to clomiphene therapy, mean serum gonadotropins were generally lower than those found in our laboratory in the ovulatory cycle. Therapy with clomiphene, followed by human chorionic gonadotropin, is the treatment of choice, although the response is not predictable. Seven of 9 patients have ovulated, resulting in 3 conceptions.
amenorrhea and galactorrhea following parturition as a distinct entity. Some decades later, Frommellb again brought this condition to light, and it is now known as the Chiari-Frommel syndrome. Then, in 1932, Ahumada and de1 Castillo? pointed out that amenorrhea-galactorrhea could exist in nulliparous women. Attention was again in 1953 focused on the occurrence of nonpuerperal amenorrhea-galactorrhea by Argonz and de1 Castillo.3 In 1954, Forbes and associates” observed similar cases but noted a high incidence of pituitary tumors in their series. Arbitrarily, the association of a pituitary tumor with amenorrhea-galactorrhea is designated as the Forbes-Albright syndrome. In 1966, Shearman’ reported amenorrheagalactorrhea following the administration of oral contraceptives. To date, a total of 41 cases of “post-pill” amenorrhea-galactorrhea have appeared in the literature.5-12 This study of 10 women with amenorrhea-galactorrhea following usage of the contraceptive
HIP P oc RATE s made the astute observation, “If a woman who is not with child, nor has brought forth, have milk, her menses are obstructed.” Thus, he was the first to record the syndrome of amenorrhea and galactorrhea existing simultaneously. In 1855, ChiarP recognized the persistent
From the Department of Endocrinology, Medical College of Georgia. Support furnished in part by Research Grant No. AM-04429-10 from the National Institute of Arthritis and Metabolic Diseases, United States Public Health Service, and in part by General Research Support Grant No. 5-501RRO-5365-10, United States Public Health Service. Presented at the Thirty-third Annual Meeting of the South Atlantic Association of Obstetricians and Gynecologists, Atlanta, Georgia, February 7-10, 1971. The opinions or assertions contained herein are those of the authors and are not to be construed as oficial or reflecting the views of the Department of Defense. *United States Fellowship.
Air Force
Research
838
Post-pill
pill attempts to define the deficiencies the treatment of this syndrome. Materials
and
in and
methods
Ten patients with amenorrhea and galactorrhea following oral contraceptive therapy were studied; 9 were hospitalized for an endocrine survey.* Serum gonadotropins and basal body temperature prior to, durin,?, and following clomiphene therapy were obtained daily in the 5 patients who were able to stay in the hospital for a period of 21 or more days. In addition, urinary steroid assays, vaginal smears, and cervical mucus studies were obtained frequently. Endometrial biopsies were taken prior to and after treatment. Subsequent to this initial hospital study, therapy was continued, and various parameters of response were utilized to indicate ovulation. Each patient had an infertility investigation prior to therapy, consisting of husband’s evaluation, postcoital cervical mucus studies for spermatozoa, and hysterosalpingogram, in addition to the studies detailed in this report. Fractionation and individual estimation of various urinary steroids were done by the method of Mahesh and colleagues’38; urinary estrogen determinations were performed by the method described by Mahesh I::b Findings
and
results Menstrual history. Patients into two groups based on the orrhea. Group A patients are “post-pill” because amenorrhea set after therapy with oral
were divided onset of amendesignated as had its oncontraceptives.
*Materials for radioimmunoassays of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were generously supplied by the National Pituitary Agency and National Institute of the Endocrinology Study Section, Health: (1) Human follicle-stimulating hormone, LER 869-2, 1 mg. = 2,782 I.U. of FSH and 92 I.U. of LH; (2) Human luteinizing hormone, LER 960, 1 mg. = 923 I.U. of LH and 1.9 I.U. of FSH; (3) Human pituitary FSH antiserum (rabbit) ; (4) Human chorionic gonadotropin antiserum (rabbit); (5) Human pituitary extract reference preparation, LER 907, 1 mg. = 20 I.U. of FSH and 48 I.U. of LH. These techniaues are based on the radioimmunoassay principle. with the use of specific doubleantibody systems. We are indebted to H. F. L. Scholer for assistance in the radioimmunoassay of serum gonadotropins. The cis and tram isomers of clomiphene citrate were supplied by the Wm. S. Merrell Co., Cincinnati, Ohio.
and
pill-related
amenorrhea-galactorrhea
839
Group B patients are designated as “pillrelated” because oral contraceptives wcrc administered in the management of preexisting amenorrhea. In both groups of patients, the galactorrhea had its onset either during therapy or after discontinuation of therapy, and all were amenorrheic foilowing cessation of the pill. Five of the 10 patients had previously conceived, and all but one of the nulligravidas had regular cycles indicating a high incidence of previous ovulatory cycles in the entire group (Table 1).
Type and duration of oral contraceptives. At least 4 different pills or dosages were involved, failing to implicate a specific compound. The combined pill was employed in 6 patients, the sequential in two: and unknown, in the other two (Table II Duration of therapy varied from 6 months to 4 years, with half being on therapy lor two years or less. Duration of amenorrhea-galactorrhea. Of the 10 patients under study, 6 had “postpill” amenorrhea of 4 or more years (Table I). Galactorrhea was noted during oral rontraceptive therapy in 3 patients and following cessation of therapy in 3: and in the remainder galactorrhea was not dixovered until the breasts were compressed durin,? examination.
Serum gonadotropins and other findings. Radioimmunoassay of serum gonadotropins was performed in 8 patients, and results were normal to low. Serum FSH was within the range found in our laboratory for the follicular phase of the ovulatory cycle (Table II), though 3 patients (D. S.? C;. P. and D. McE.) had values considerably lower than our mean laboratory value (6.:i m1.U. per milliliter of serum). Mean serum LH values in the 6 patients with serial determinations were all lower than the mean serum LH values for our laboratory (6.5 m1.U. per milliliter). Vaginal smears ransed from moderately hypoestrogenic to almost castrate in all patients, and endometrial biopsies were atrophic or moderately hypoplastic (Table II). Urinary estrogens were low in 3 of the 5 studied. X-ray of the sella turcica was normal, as were thyroid studies and estimation
840
Gambrell,
Greenblatt,
Table I. Clinical
and
history
Mahesh
of post-pill
and pill-related
amenorrhea-galactorrhea
Patient Post-pill G. C.
13
28-42
Norethindrone, 2 mg., and mestranol, 0.1 mg.
V. G.
26
0
11
28
Norethindrone, 2 mg., and mestranol, 0.1 mg.
15
48
52”
D.
S.
23
0
13
Irregular
Norethindrone, 2 mg., and mestranol, 0.1 mg.
12
7
7
L. T.
26
1
11
28
36
48
48
c.
s.
29
1
12
30
“Combined”
8
51
Pill-related G. P.
34
Abl
11
Amenorrheat
Norethynodrel, 2.5 mg., and mestranol, 0.1 m.5.
42
72
P. w
39
0
12
Amenorrheag
30
30
D. McE.
27
0
12
Amenorrheat
Chlormadinone, 2 mg., and mestranol, 0.08 w
48
48
S. H.
32
1
14
Amenorrheaz
Norethynodrel, 5 mg., and mestranol, 0.075 mg.
6
54
t
L.
26
0
14%
Amenorrheat
Chlormadinone, 2 mg., and mestranol, 0.08
24
36
t
B.
*Galactorrhea +Galactorrhea $Had
fairly
of urinary steroids.
onset
while
detected regular
taking on
cycles
?
t 72
t 60”
pills.
initial
physical
before
onset
17-ketosteroids
?
and
examination. of
amenorrhea.
17-ketogenic
Changes in serum gonadotropins and various urinary steroids during and following clomiphene therapy in the 5 patients hospitalized for 21 days. In Patient G. C. the basal body temperature did not change following treatment for 6 days with cisclomiphene, 25 mg. (Fig. 1) . Serum gonadotropins showed little responsiveness to therapy, FSH remaining rather tonic. Serum
LH was low prior to therapy; some sporadic spikes occurred afterward. Urinary estrogens remained low during and following treatment. Both the 17-ketosteroids and 17-ketogenie steroids were within the range of normal with only a slight increase in 17-ketosteroids following therapy. Treatment in the second cycle consisted of trans-clomiphene, 20 mg. for 10 days followed by human chorionic gonadotropin (HCG) 4 days later without any evidence of ovulation. In the
\ olume kumber
110 6
Post-pill
Table II. Laboratory, cytology, amenorrhea-galactorrhea
and
pill-related
and tissue studies of post-pill
amenorrhea-galactorrheo
841
and pill-related
Patient Normal
follicular
values
6.3(51)*
Post-pill G. c. V. G. D. S. L. T. c. s.
2+ 2+ 3+ 3+ 2+
Hypoplasia Hypoplasia Hypoplasia Hypoplasia
5.7(5)* 5.9(6) 4.9(6) 9.7(l) 6.4( 3)
Pill-related G. P. P. w. D. McE. S. H. L. B. -
I+ 3+ 2+ 2+ 2-k
Atrophic Atrophic Hypoplasia Atrophic
“Number
of determinations
6.5(48)*
3.2(5)” 2.3(6) 5.7(6) 11.0(l) 5.5(3)
9.3(z)* 10.8( 2) 6.7(2)
3.8(6)
2.1(6)
4.3(6)
4.5;)
6.8(2) 8.6( 2) 1?.1(2)
8.0;)
11.671)
13.0;)
9.1(?)* 8.8(?) 7.4(“) 6.5(2)
fi.4(‘i1” 9.-l(2) 16.!(2)
6.3(2) l&5(2) 11.1(Z)
i.!.T(:j ‘--~6.1(3)
5.572)
-I__
6.6(l)
--...-.---.
.~ _ .---
in parentheses.
third treatment cycle, this patient had an ovulatory response to cis-clomiphene (50 mg. for 10 days) and HCG (5,000 I.U. 5 days later), as judged by basal body temperature. There was nothing indicative of an ovulatory response in Patient V. G. treated with trans-clomiphene, 100 mg., for 5 days (Fig. 2). There was no posttreatment change in the basal temperature graph, and the endometrium remained hypoplastic on biopsy. Serum FSH continued with sporadic spikes and serum LH remained low. There was no change in any of the urinary steroids. This patient has been treated with clomiphene and both its isomers for several cycles without obtaining an ovulatory response. Following cis-clomiphene therapy in Patient D. S., there was some slight rise in both serum FSH and LH (Fig. 3). Urinary steroids were within the range of normal and did not change. Since the patient had no rise in basal body temperature following 10 mg. of cis-clomiphene for 5 days, HCG. 5.000 I.U., was given IO days afterward. A short sustained rise in temperature was noted 7 days later, lasting only 6 days. Treatment was sufficient to induce menses in this amenorrheic patient but the endometrial biopsy was proliferative. Subsequent treatment with cis-clomiphene, 10 mg., for 5
days alone resulted in 3 presumptive ovulatory cycles, because of the biphasic temperature curves; however, she has not as yet conceived. The response of serum gonadotropins to therapy with 100 mg. of cis-clomiphenc for 5 days is of significance in Patient G. P. (Fig. 4). Serum FSH increased slightly following therapy to levels found in the follicular phase of the normal ovulatory cycle with a mid-cycle FSH surge similar to that found in ovulatory cycles. However, serum LH remained very low and quite tonic. Urinary estrogens and fractionation of the other urinary steroids indicated little change. Prior to and since this study cycle, this patient has not shown any indication of ovulation with multiple treatment cycles with clomiphene and both its isomers, with or without HCG. However, she has ovulated according to biphasic temperature, cervical mucus, vaginal cytology, and endometrial biopsy in two out of two cycles treated with human menopausal gonadotropins, 16 to 18 vials in 10 days, and HCG, 5,000 T.U., though she did not conceive. In Patient D. MC&, there was a~uiincrease in serum FSH during therapy with 20 mg. of cis-clomiphene for 5 days but LH remained quite low and rather tonic (Fig. 5). Urinary estrogens assayed at nearly double
842
Gambrell,
Greenblatt,
and
Mahesh
POST-PILL AmrfwrhwGolactorrhra
POST-PILL Amenorrhea-Goloctorrhea
n
GC Ape 24
tE r E”
C 17.Ketogeaic Steroids
50.
o-,.,,,~..,...,................, DAYS
Fig. 1. Anovulatory response to cis-clomiphene in a patient with amenorrhea-galactorrhea secondary to oral contraceptive therapy. Note sporadic increases of LH during and following clomiphene therapy without change in FSH (E-, hypoplasia; E, proliferative).
values while on therapy with a peak similar to the preovulatory one observed in the normal ovulatory cycle, occurring on the thirteenth and fourteenth day after treatment was initiated. There was no significant change in 17-ketosteroids or 17-ketogenic steroids. Since this patient had no indication of ovulation by the fifteenth treatment day, either by basal temperatures, vaginal smears, or cervical mucus, HCG, 5,000 I.U., was administered. On biopsy, the endometrium had converted from hypoplasia to proliferative on this day. This patient conceived during this treatment cycle, most probably the first or second day following HCG administration, though the basal tem-
OIYS
Fig. 2. Anovulatory response to trans-clomiphene in a patient who noted galactorrhea during oral contraceptive therapy. Amenorrhea followed cessation of oral contraceptive therapy with persistence of galactorrhea. Note that serum LH remained low following therapy with a mean value of 2.8 m1.U. (normal follicular levels, 6.5 m1.U.) while serum FSH stays within the range of normal with a mean value of 6.1 m1.U. (normal, 6.3 m1.U.) (E-, hypoplasia) .
perature graph is not available to aid in detecting the day of ovulation. Labor was induced by oxytocin infusion March 14, 1971, with delivery of a normal 9 pound, 4 ounce female. Treatment and results. Of the 10 patients, 9 presented for infertility and one, because of lactation. They were treated with various regimens to induce ovulation (Table III). The difficulty in inducing ovulation in these patients is well demonstrated by the multiplicity of regimens and the frequency of failure. To date, all 5 of the pill-related
Volumr Nulnhcr
Post-pill
Il(l h
and
pill-related
t ‘t”i”Qt
843
PILL-RELATED Amenorrhro-Galactorrhro
POST-PILL Amrnorrhea-G‘~loctorrhM
cis-Clomid
amenorrhea-galactorrheo
HCG
5.000 1
IU
DAYS
Fig. 3. Anovulatory response to cis-clomiphene in a patient that became amenorrheic with galactorrhea following one year of oral contraceptives. Note the increase in serum LH during therapy and FSH following therapy. Seven days after HCG, basal temperature rose for 6 days only and biopsy of endometrium at onset of menses was proliferative (E-, hypoplasia; E, proliferative).
amenorrhea-galactorrhea patients have ovulated and 3 have conceived. Only 2 of the 4 post-pill patients have ovulated, but neither has conceived. Comment
After a decade of ever-increasing utilization of oral contraceptives, in which the decrease in side effects has paralleled the lowering of dosage, more and more attention has been drawn to a variety of complications. Post-pill amenorrhea of varying duration, first reported in 1966,5?I4 has been confirmed by several authors. 6a~7l * This condition is rare, and, if left untreated, many patients will spontaneously menstruate. Larsson-CohnI studied the length of the
DAYS
Fig. 4. Anovulatory
response to cis-clomiphene in an amenorrheic patient who developed galactorrhea after oral contraceptive therapy. Note the increase in serum FSH following clomiphene with a mid-cycle FSH surge similar to that found in ovulatory cycles while LH remained quite low and tonic.
first 3 menstrual cycles after combined pill therapy in 516 women. Only 4 of these women had amenorrhea for 6 or more months but 3 had irregular mensesbefore therapy. Furthermore, Rice-Wray and her associatesl@reported “the return of ovulatory function appears to be equally prompt whether contraception was used for 1 to 4 or 5 to 6)$ years.” In their study of 163 women, more than 75 per cent ovulated in the first posttreatment cycle and 98 per cent ovulated within the first 3 cycles, In our
844
Gambrell,
Greenblatt,
and
Mahesh Amer.
PILL-RELATED Amsnorrhca-GalactorrhW D.McE Age: 27
Sosol Body Temperature
EDC 20 Fcb 71
ssss
Y E
97-J Ii 4 10.0 ‘0 -c 2" 0I
;
:\
~:
F
Implontotion Spotting
I
‘k/t)
‘A
‘+
50
:
0
z 2 +IE
,.
-1
FSH---
LH -
I
I:
n
n z , 0.0 : P 5.0 1 OJ
,o.or 0’ N
17- Keto,laoidr
dll n
J-
r-
n 1
5.0.
I7-Kotogenic
Steroids
P on-n.:.,,~:,,.:~:.:~I 9 13 MAY
17
1970
2,
25
29
I 3 5 JUNE
Fig. 5. Response to cis-clomiphene in an amenorrheic patient developing galactorrhea while taking sequential contraceptives. Note the increase in serum FSH during the therapy while LH remained low and rather tonic. Urinary estrogens increased during clomiphene administration with a peak similar to that observed preovulatory, the thirteenth and fourteenth days after initiation of therapy. HCG, administered 10 days after clomiphene, was sufficient to induce ovulation in that the patient conceived in this cycle and was delivered March 14, 1971 (E-, hypoplasia; E, proliferative) .
July 15, 1971 J. Obstet. Gpncr.
own experience with several thousand patients taking oral contraceptives for more than 4 years, post-pill amenorrhea has indeed been rare. More important, from the standpoint of prognosis and therapy, than post-pill amenorrhea is amenorrhea coexistent with galactorrhea. Three of our patients noticed the onset of galactorrhea while taking birth control pills; 4 were unaware of the presence of milk until it was demonstrated on the initial breast examination. Friedman and Goldfie+ reported that 3 of their 9 patients with galactorrhea noted breast secretions during contraceptive therapy, but 4 were not aware of lactation until examined for it. It is apparent that galactorrhea is far more prevalent than previously supposed, and the breasts of each new patient should be compressed, especially those with amenorrhea. Since 5 of our 10 patients had previously been pregnant, the finding of galactorrhea in nulliparous women, with or without amenorrhea, is significant. Post-pill and pill-related amenorrheagalactorrhea simulates the isolated pituitary syndrome, characteristic of the Chiari-Fromme1 syndrome. In both, the influence of prolonged estrogens and progesterone-endogenous in one, exogenously administered in the other-disrupts the hypothalamic-pituitary axis, resulting in amenorrhea and galactorrhea. The length of suppression of the hypothalamus with these potent steroids need not be excessive, in that 5 of our 10 patients were receiving therapy for 2 years or less, 3 of these less than one year. In the 10 patients with post-pill amenorrhea-galactorrhea reported by Shearman and Turtle,l” the duration of contraceptive therapy was less than 2 years in 7 of them. It appears that patients with prior menstrual irregularities are more prone to develop post-pill amenorrhea-galactorrhea. Half of our patients had amenorrhea (Group B) and had been treated with oral contraceptives to induce menstrual periods before consulting us. In addition, 2 of our 5 postpill patients (Group A) had menstrual irregularities prior to contraceptive therapy,
Post-pill
Table
III.
Treatment
and
pill-related
amenorrhea-galactorrhea
845
and results _...--. -_. -.
Patient
Clomiphene/
Post-pill G. C. V. G. D. S. L. ‘I-. c. s.
0
Pill-related G. P. P. w. D. McE. S. H. I,. B. -__
0 Z= anovulation;
Transclomiphene/
and HCG
and HCG
Cisclomiphene/
0 Not
HMG
and HCG
+
0 0
and HCG
(1 -i-
0
treated as yet
0
0
0 n 0 + = ovulation.
0 0
0
n n
0
4 f -1-X
il
0
i*
+* HMG
=
human
menopausal
yonadotropill.
____
~_- . . .._
.~ .-
“Conwived.
though 3 did have previously regular cycles. Friedman and GoldfienGa and Halbert and Christian? noted menstrual irregularities in a high percentage of their patients prior to pill therapy. However, Shearman and TurtWo found only one in their series that had irregular cycles. It would seem prudent, therefore, to utilize some other therapy rather than oral contraceptives to regulate the irregular menstrual cycle. No consistent pattern was found in serum gonadotropins, though there is a tendency for both serum FSH and LH to be slightly lower than mean values in our laboratory for the follicular phase of the normal ovulatory cycle. All 6 of the patients with serial determinations had mean serum LH values below normal and 4 (Figs. 1, 2, 4, 5) had rather low, tonic serial serum LH patterns. The serum gonadotropin pattern in these anovulatory women appears to be different from that in the Stein-Leventhal syndrome where FSH rather than LH is found to be consistently low. These results are not surprising since in the isolated pituitary syndrome low serum gonadotropins and elevated prolactin would be expected. Urinary estrogens were low in 3 out of our 5 patients studied, results which are in agreement with those of Shearman and Turtle.l” Vaginal smears in our patients were generally hypoestrogenic as were endometrial biopsies in that 3 out of 8 were atropic
while the remainder showed hypoplasia, a finding also observed by Halbert and Christian.7 In patients that generally ovulate with clomiphene, there is a small but significant rise in serum FSH and LH during administration of the drug, followed by an ovulatory surge of both FSH and LH 10 to 15 days from the start of treatment. One patient (Fig. 3) had such a rise of both serum FSH and LH during therapy, but no surge was observed during the period of observation. Even though HCG was given 10 days after clomiphene, there was no evidence of ovulation in this cycle. Subsequent treatment with this agent alone in the next 3 cycles resulted in 3 presumptive ovulatory cycles as evidenced by biphasic temperature curves. Another patient (Fig. 4) had a rise in serum FSH during treatment followed by a midcycle surge of FSH similar to that seen in ovulatory cycles, but serum LH was low and continued quite tonic. This patient did not receive HCG, and there was no evidence of ovulation by any of the criteria utiked. The patient who conceived during the study cycle (Fig. 5) had a rise in serum FSH during clomiphene administration which returned to low levels after discontinuation of the drug. Serum LH remained low and tonic, and no surge of either FSH or LH was observed during the remaining serial serum gonadotropin collection, However,
846
Gambrell,
Greenblatt,
and Mahesh
HCG, administered 10 days after clomiphene, was sufficient to induce ovulation leading to conception. A survey of the data presented in Table III shows that whereas clomiphene alone did not induce ovulation in 6 out of 7 patients ovulations were obtained in 4 out of 6 patients, resulting in 2 conceptions, when HCG treatment was added. The possibility that the LH-like activity in HCG contributed to these ovulations in patients who had rather low tonic LH levels may be considered. The response to the therapy of infertility in patients presenting with pill-related amenorrhea-galactorrhea varies from poor to moderate.‘Op I1 Of the 19 patients with
post-pill amenorrhea (9 with galactorrhea j, Friedman and Goldfien@ obtained conceptions in 8 of the 15 that were treated. They did not separate their amenorrhea-galactorrhea patients from the simpler post-pill amenorrhea. In our own series, only 3 of 9 patients desiring pregnancy have conceived to date though ovulation presumably has been induced in 7 of the 9. Only one patient had ovulated with clomiphene alone, 4 required clomiphene and HCG, and 2 needed menopausal gonadotropins and HCG. Our present routine is to use clomiphene first, or one of its isomers, adding HCG if there is no response. In those patients who do not respond to either of these, menopausal gonadotropins and HCG are given.
REFERENCES
la. Chiari, J., Braun, Cl., and Spaeth, J.: In Speert, H., editor: Obstetric and Gynecologic Milestones, New York, 1958, The Macmillan Company.. lb. Frommel, J. T.: In Speert, H., editor: Obstetric and Gynecologic Milestones, New York, 1958. The Macmillan Comnanv. 2. Ahumada, J. C., and de1 C&lo, E. B.: Bol. Sot. Obstet. Ginec. 11: 64, 1932. 3. Argonz, J., and de1 Castillo, E. B.: J. Clin. Endocr. 13: 79. 1953. 4. Forbes, A. P., ‘Henneman, P. H., Griswold, G. C., and Albright, F.: J. Clin. Endocr. 14: 265, 1954. 5. She&man, R. P.: Lancet 2: 1110, 1966. 6a. Friedman. S.. and Goldfien. A.: T. A. M. A. 210: 1888, 1969. 6b. Friedman, S., and Goldfien, A.: AMER. J. OIISTET. GYNEC. 104: 846, 1969. 7. Halbert, D. R., and Christian, C. D.: Obstet. Gynec. 34: 161, 1969. I
Y
Discussion
DR. LEO J. DUNN, Richmond, Virginia (By invitation). The importance of the hypothalamic centers in the regulation of pituitary function has been recognized since the early 1930’s. The identification of specific centers in the hypothalamus controlling specific factors has been a further advance in our knowledge. More recently, isolation, purification, structural analysis, and even syntheses of releasing factors promise new experimental tools and therapeutic approaches to problems of dysfunction in this area.
8. MacLeod. S. C.. Parker. A. S.. and Perlin. I. A.: AMER. J. O~STET. G~NEC. IO6: 359, 1970. 9. Nyirjesy, I.: Obstet. Gynec. 32: 52, 1968. 10. Shearman, R. P., and Turtle, J. R.: AMER. J. OBSTET. GYNEC. 106: 818, 1970. 11. Arrata, W. S. M.: Ob.Gyn. News 5: November 1, 1970. 12. Greenblatt, R. B., Scholer, H. F. L., and Mahesh, V. B.: Proc. 52nd Meet. Endocrine Sot. June, 1970. 13a. Mahesh, V. B., Greenblatt, R. B., Aydax, C. K., Roy, S., Puebla, R. A., and Ellegood, J. 0.: J. Clin. Endocr. 24: 1283, 1964. 13b. Mahesh, V. B.: Steroids 3: 647, 1964. 14. Whitelaw, M. J., Nola, V. F., and Kalman, C. F.: T. A. M. A. 195: 780. 1966. 15. Larssoi-Cohn, U.: Acta ‘Obstet. Gynec. Stand. 48: 416, 1969. 16. Rice-Wray, E., Correu, S., Gorodovsky, J., Esquivel, J., and Goldzieher, J. W.: Fertil. Steril. 18: 212, 1967. Early experimental work in the hypothalamus demonstrated that creation of destructive lesions in particular areas would lead to specific functional changes. It was further recognized that similar functional derangements could also be created by the administration of a variety of drugs seemingly unrelated to the endocrine system. These discoveries have shown that some dysfunctions of the pituitary can be attributed to abnormalities of hypothalamic control and that these malfunctions may come from organic
Post-pill
lesions such as the tumors associated with the Forbes-Albright syndrome, nonhormonal chemical influences as with the phenothiazines, emotional disturbances, or intrinsic malfunctions or hormonal influences as illustrated in the precedinf paper. The authors have presented two apparently different groups of patients. One group had a primary or spontaneous menstrual disturbance perhaps worsened by exposure to oral contracvptivcss; the other had a secondary onset menstlual disorder possibly induced by oral contraceptives. Such spontaneous or primary disorders may be analagous to the Ahumada-de1 (Lstillo syndrome whereas the secondary type m,ty be analagous to the Chiari-Frommel syndt omr. The finding of breast secretion upon careful examination of a parous woman is not necessarily a pathologic finding as demonstrated by Friedman and Goldfien.1 A higher association with pathology appears to exist when: (1) breast srscretion is found in a nulliparous female with no drug exposure, and (2) a symptomatic flow of milk (galactorrhea) is found in any woman M ho has not recently breast fed. The inclusion by most authors of cases of alnenorrhea with those of amenorrhea and galitctorrhea seem to reflect the opinion that they rc,present varying manifestations of the same underlying pathology when studies of thyroid, adrenal function, etc., are normal. Further ssparation of these patients may be possible with progress in our understanding of the hypothalamic factors and their availability for clinical use. For the present time it might be useful to cl,nsitler as a separate group the previously mentioned patients who have more obvious pathologic lactation and galactorrhea. The effects of lactation on hypothalamic and gonadal function are as yet unclear. We need to remember the work of torbrs and co-workers,* and Keettel and BradI>ury,,! suggesting ovarian refractoriness to gonatlotropins in the presence of lactation as a possible explanation for some treatment failures. The issue remains as to whether or not the use of oral contraceptives is causally related to the reported cases of amenorrhea or amenorrheagalactorrhea. The marked effect of sex steroids on the pituitary have been known since the studies of Greep and Jones.4 in 1950. Patients I\rith previously normal menstrual cycles and normal fertility have developed the syndrome. One would, therefore, have to accept the hypoth-
and
pill-related
amenorrhea-galactorrhea
847
esis that a very small group of otherwise normal females will develop a serious menstrual aberration following the use of oral contraceptives. Perhaps of greater importance is the awareness that patients with pre-existing menstrual abnormalities, while representing only a small percentage of oral contraceptive users, constitute a large percentage of the post-pill amenorrhea cas(‘s. In the report of Halbert and Christian,5 25 of 35 cases had a preceding menstrual abnormality and 7 of these were given oral contraceptives for the purpose of regulating menses. The importance of careful evaluation of menstrual discbrtlcrs rather than the casual treatment with oral ho+ mones should bc emphasized. The authors of this paper have not only reviewed their experience with this interesting syndrome but have shown the evaluation nt*c rssary to rule out other endocrinopathies, brain tumm,, and coincidental health problems before establishing a diagnosis and proceeding with therapy. I would like to ask Dr. Greenhlatt to comment on the relationship between the low rstrogcn activity in his patient groups and its c*ffrbct on the results with therapy. REFERENCES
1. Friedman,
S., and Goldfien, A.: AMER. J. 104: 846, 1969. Forbes, A. P.. Henneman, P. H., Griswold. G. C., and Albriqht, F.: J. Clin. Endncr. 14: 265, 1954. Keettel, W. C., and Bradbury, J. T.: +%MER. J. 0Bs.rE.r. GYNEC. 82: 99.5, 1961. Greep, R. O., and Jones, C.: Recent Progr. Hormone Res. 5: 197, 1950. Halbert, D. R., and Christian, C. D.: Obstet. Gynec. 34: 161, 1969. OBSTET.
2. 3. 4. 5.
GYNEC:.
DK. LUTHER M. TALBERT, Chapel Hill, North Carolina. Oral contraceptive compounds have now been generally available for ten years, and their side effects and the complications oi’ theil use ;ire rapidly being delineated. An irlcrea.Ged incidence of thromboembolic disease is wtl11 documented, and the inc.reased annual death rate in young women taking oral contraceptives is probably about 1.5 to 3jlO0,OOO w0men.l Some reports have suggested an association with cerebral vascular throml)oses, hut a relationship is unproved.2 Spellacy” and others have shown striking alterations in glucose metabolism including elevation of plasma glucose, growth hormoncx, and insulin, giving rise to as yet undocumented fears of permanent changes after long-trrm therapv.
848
Gambrell,
Greenblatt,
and
Mahesh
Protein-bound iodine and BEI are increased because of the rise in binding proteins. Pill amenorrhea is probably more common than the few reports in the literature suggest. Although Dr. Greenblatt’s patients with galactorrhea and amenorrhea responded poorly to clomiphene alone, Friedman and Goldfien4 state that the response to therapy in this group is the same as those with amenorrhea alone. Both reports, however, are based on small groups of patients. We have studied 10 patients with post-pill amenorrhea of over one year’ duration during the past 5 years, 3 of whom have had associated galactorrhea. Two of these patients spontaneously resumed apparently ovulatory cycles as shown by temperature charts and endometrial biopsies. Duration of amenorrhea in these 2 patients was 16 and 25 months. The third patient does not desire a pregnancy at the present time and has not been treated. Only 2 of our patients with post-pill amcnorrhea had pre-existing menstrual irregularities. Endocrine studies including 17 ketosteroids, 17 hydroxycorticosteroids, urinary gonadotropins, and thyroid function tests were consistently normal, but 6 of the 10 patients had evidence of estrogen deficiency on vaginal smears. Dr. Greenblatt’s finding of decreased serum LH levels offers an explanation for the high incidence of estrogen deficiency reported in these patients. I would like to ask Dr. Greenblatt for his recommendation for therapy in the patient with more than one year of pill-related amenorrhea but who does not desire a pregnancy. Should she be treated, and, if so, how far would the author progress in the treatment schedule outlined in his paper?
REFERENCES
1. Hellman, L. M.: Second Report of the Advisory Committee on Obstetrics and Gynecology, Food and Drug Administration, August 1, 1969. 2. Cole, M.: Arch. Intern. Med. 120: 551, 1967. 3. Spellacy, W. N.: AMER. J. OBSTET. GYNEC. 104: 448, 1969. 4. Friedman, S., and Goldfien, A.: J. A. M. A. 210: 1888, 1969. DR. GREENBLATT (Closing). In reply to Dr. Dunn’s query, let me say that in our experience the patient with low endogenous estrogen production is, somewhat handicapped in the ultimate response to clomiphene. However, we have had several instances where the individual had castrate smears and atrophic endometrium, particularly in those with Chiari-Frommel syndrome, who responded satisfactorily, ultimately conceiving and carrying to term. Dr. Talbert again brings to our attention the metabolic disturbances that occur during longterm ingestion of the pill. Allow me to emphasize the fact that despite elevated PBI and T4 findings to my knowledge no patient has ever exhibited evidence of thyrotoxicosis. Decreased tolerance for carbohydrates has been documented, but only in a rare case has this; imbalance persisted and such an occurrence may merely represent the unmasking of a latent diabetic diathesis. As far as therapy for the post-pill amenorrheic patient who does not desire conception, we feel that the simple administration of an estrogenprogestogen compound for 5 days per month is sufficient to induce withdrawal periods. In this way, the anxieties associated with the amenorrhea may be eliminated.