- Email: [email protected]
Syndrome of anovulation following the oral contraceptives
Syndrome of anovulation
following the
oral contraceptives OSCAR
I.
HERBERT Bethesda,
DODEK, L.
JR.:
KOTZ,
M.D.
M.D.,
F.A.C.O.G.
Maryland
Four cases of anovulation following use of oral contraceptives are presented, outlining the diagnostic evaluation and therapy. The mechanism for the failure of reappearance of ovulation is felt to be prolonged dysfunction of hypothalamic centers concerned with cyclic gonadotropin release. Prednisone, 5 mg. twice daily for 3 months, is suggested as initial therapy. Zf return of ovulation does not follow prednisone administration, use of Clomid or Pergonal is indicated. The favorable response of these patients to therapy suggests that, in many instances, the anovulation following the oral contraceptives is a relatively mild endocrinopathy.
DYSFUNCTION
MENSTRUAL
Menarche was at age 12. Her periods were always regular, occurring every 29 days, lasting 5 to 6 days, and accompanied by premenstrual molimina and dysmenorrhea. Following cessation of oral contraceptive therapy, the menses were grossly irregular. Between February, 1964, and her initial visit in September, 1964, the patient had two episodes of very prolonged cycles during which the diagnosis of pregnancy was entertained but never established. On initial physical examination the patient displayed a normal feminine configuration. There was mild facial acne. The hair distribution was not unusual and the breasts were well developed. Pelvic examination revealed normal external genitals with a normal clitoris. The uterus and adnexa were palpable and normal. Infertility and endocrine evaluation indicated adequate endogenous estrogen, as evidenced by excellent arborization of clear, elastic cervical mucus, and by a withdrawal menstrual flow following oral administration of 10 mg. of Provera” daily for 5 days. Basal body temperature charts between September, 1964, and January, 1965, confirmed the absence of ovulation. Skull roentgenograms revealed no abnormality of the sella turcica. A 24 hour urinary excretion of 17-ketosteroids was 12.3 mg. and the protein-bound iodine was 3.5 pg per cent. A 10 hour postcoital examination of the
fOl-
lowing use of the oral contraceptives is a disturbing syndrome which has now made its appearance in clinical practice.1’2 The problem occurs at a time when the patient has decided to increase her family and infertility secondary to anovulation or irregular ovulation is a source of great anxiety. The purpose of this paper is to call further attention to this problem and to outline the management of four such patients from our private practice. Two of the patients were described in a previous comment on the relationship between oral contraceptives and infertility and we now are able to report the menstrual course of these patients following successful pregnancy.’ Case
reports
Case 1. A 22-year-old, gravida 0, Caucasian woman was referred on Sept. 29, 1964, for infertility evaluation. She had been placed on Enovid” (dosage unknown) as an oral contraceptive at the time of her marriage in June, 1963. The contraceptive pills were discontinued in Frbruary, 1964. From the Department of Obstetrics Gynecology, Washington Hospital Center.
and
*Norethynodrel and mestranol, G. D. Searle d Company, Chicago, Illinois.
‘6n-methyl-l7-acetoxyprogesterone, Kalamazoo, Michigan.
1065
The
Upjohn
Company,
1066
Dodek
and
Kotz
Am.
cervical tnucus revc,aled 2 to 5 progressively motile sperm per high-power field, and semen analysis was normal. A Ruhin carbon dioxide tubal insufflation indicated tubal patency by auscultation, thermograph, and prompt bilateral shoulder pain. I,-thyroxinc therapy, 0.1 mg. per day, !~as initiated on Dee. 24, 1964. The patient remained anovulatoty until prcdnisone,” 5 mg. twice daily, her first ovulatory was s:tartcd Jan. 29, 1965, menses occurring on Frh. 25, 1965. She was conovulatory tinued on prcdnisonc an d also had cycles in March, April, and May as evidenced by a biphasic basal I)ody rctttpcraturc curve and cndometrial biopsy. The patient conceived in rarly June, 1965, and had a normal vaginal delivery of a 5 pound, 10 otmcc fcmalr in good condition on Jan. 14, 1966. Prednisone had brrn continued through the fourteenth week of pregnancy. The patient’s II~CIIWS rcturttrd without thcrapy within 2 months of deli\rery attd were fairly regular, although ttot of the precise regularity that was present bcforc her marriage. She conceived again in July, 1966, and is now in the second crimrstcr of an uncomplicated prcgttancy. Case 2. A 23-year-old, gravida 0, Caucasian woman was rcfcrred on March 29, 1965, for an infertility evaluation. She had used Enovid, 5 for contraception from the time tng. cyclically, of her marriage in 1962 until July, 1964. The menarchc was at age 13 and the periods were always regular, occurring every 30 days, lasting 5 days. and associated with premenstrual tnolimina and dysmenorrhea. Following cessation of the Enovid her periods became grossly irregular, attd the patient had complete amrnorrhea from Novemh(br, 1964, until hrr first visit in March, 1965. She also romplaintd of facial arne and slight ditninution of hrrast size since discontinuing oral contraception. On physical examination the patient displayed a normal femininr c,onfiguration. There \vas marked facial acne. The hair distribution was normal and the breasts wcrc well developed. recavalrd normal external Pelvic examination genitals and the clitoris was not enalrged. Tht, uterus and adnexa \verc normal. Enhocrinc and infertility evaluation indicated adequate cndogrnous estrogen, as evidenced by arborization of the cervical murus and by a withdrawal flow following oral administration “A’-hydrocortisone,
West-Ward,
Inc.
.4ugu\t J. Obrt.
15. IYtii & (;ywr.
of Provera, 10 mg. daily for 5 days. Thr patie-nt had measured her hasal body tcmpcraturr front Jan. 18, 3965, through March 29. 19G5, \\hilc she was amenorrheic, and thrrc \vas no cvidcrtc~~~ of a biphasic curve. Skull rorntgcnogratns revcalcd no abnormality of the sclla turrira. .4 24 hour urinary rscrrtion of 17-kctostcroids \vas I -I.(i mg. and the prntcin-bound iodinr w;ts 5.1 ,A!: p;‘r crnt. A 10 hour postcoital examination rc,vrtalrd inttutttcrablr progressively niotilca yp’rnt p-1 high-power tir>ld and a sprrm cr,unt contirmcd the. absenrc, of a male factor. ?‘lt(, Rubin tc’\i \VBS diagnostic of tubal patcmcy. ‘I’h,, patient was started on prednisonc*. 5 1112, twiccx daily, on May 10, 1965. and had an ovtrlator); plbriod on June 16, 1965. as irtdic.atcd by a biphasic basal body temprraturcx cur\-tx. Shr ronccivtxd in ~trly July, 1965. and way drlivtsrcd \ragittallv of a ti pound, 8 ounce frmalc on March ‘1.5, 19ti6, Tvithout complication. PAnisonr had brcn taken through the fourtcc~tttlt \VWk of pregnancy. Her mcnscs rrturnc.d promptly following dclivcry and have brtxn r,‘gular. An intrauterine d&cc has been 1tht.d fat conlraccption. Case 3. A 23-yrar-old, gravida 0, woman was rcfrrrcd for an infrrtility evaluation on June 6. 1966. ‘I‘hc, patient hqan using oral contraq~tivct.q at the timr of hrr nt:trriagr in JUIW. 1963, and took them until Jan. IO, 1966. in routinc cyclic fashion. She took Enovid f 10 111g. ) . Enovid (5 mg.), or Ortho-Novum” j2 my.) during this time. The rhoicy of cotttracc’ptivc.s dcpendcd on thr sampl(>s availahlc in thr of& of a physician mcrnbrr of thr family. The patirnt had no sidt, rffects from an) of them. She had atnrnorrhra from thr timr shr stopped (hf. pills until her initial viGt itt Junr. I otiti. Menarchr occurred at agr 12. Hrr periods had always occurred monthly and wrrr accotttpanicad by premenstrual tnolimina. She had nrvct previously skipped a monthly flow. On initial physical examination the patittnt had a normal feminine confqtration. There w’as no hirsutism or acne and thr breasts were wc,ll drvrlopcd. The rxtrrnal genitals w?rr normal :tttd the clitoris w;ts not enlarged. The uterine frmdus cons antrflrxr~d. firm, qmntctrical? ntobilr. and slightly smallrr than normal. Thr ovaries wrrr not enlarged.
Anovulation
Endocrine and infertility evaluation reflected ;L low level of endogenous estrogen production. There was scant and viscid cervical mucus. A scraping obtained from the midlateral vaginal wall rc,vcalrd 95 per rent intermediate cells and 5 per cent superficial ~11s. A thorough exploration of the endometrial cavity with a suction curettc produced only scant fragments of hypotrophic endometrium. Provera, 10 mg. daily for 5 days, \vas prescribed in March, 1966, with only one episode of slight staining following withdrawal. Protein-bound iodine in March, 1966, was 3.7 pg per cent. The patient had been given triiodothyronine, 25 pg daily, and was taking this medication when first seen. Twenty-four hour urinary 17-ketossteroid excretion was 11.0 mg. A skull rentgenogram showed no enlargement of the sella turcica. Urinary excretion of FSH (gonadotropins) was between 6 and 16 mouse uterine units in 24 hours. Prrdnisonc, 5 mg. twice daily, was administered from June G, 1966, through Aug. 10, 1966, without effect on the basal temperature cute or the cervical mucus. From Aug. 10, 1966, through Aug. 20, 1966, Pergonal” was given in a dosage of 75 I.U. intramuscularly t\\ic.c, daily. On Aug. 19, 1966, a 10 hour postcoital examination of the cervical mucus revcalrd a profuse amount of clear, glary, elastic mucus. Thrrc were 5 to 10 sperm in each highpotvcr field, of which 40 per cent were proRrrGvcly motile,. The patient was given 5,000 units of APLt intramuscularly every 12 hours for four doses, the first being given simultaneously with the last injection of Pergonal, The couple was instructed to have coitus nightly. The basal tcmpcraturc rose on Aug. 23, 1966, and remained elevated. An immunologic pregnancy tct was positive on Sept. 20, 1966. The patient i< now in the first trimester of her pregnancy. Case 4. A 26-year-old, gravida 0, Caucasian woman was refcrrrd on June 10, 1966, for an infrrtility evaluation. She had her menarche at aqc 15, and had menstrual dysfunction before her marriage with the following general patterns: Periods would come monthly for 2 months, but during the third month the patient Lvould have only an episode of staining. During “Human menopausal qonadotropin, Cuttrr Laboratories, Rcrkelry, California. This patient was included in a Pergonat study conducted by Dr. Nathan Kasr. Associate Professor. Ob\tctrics and Gynecology, Yale University Scbont of Meditine. uho supel\,ised the therapy. Neu
tHumari York,
chorionic Nrw York.
gvnadotropin.
Aycrst
Labolator
ies,
after oral contraceptives
1067
a typical year there would be 6 to 8 periods accompanied by premenstrual molimina. She began taking Ortho-Novum, 2 mg., for oral contraception at the time of her marriage in October, 1964. She tclok the pills in the standard cyclic dosage until thv end of June, 1965. The patient had no spontaneous menses from that time until her initial visit. However, she had staining every few weeks for the entire year. In December, 1965, there had been withdrawal flow following five days of Provera, 10 mg. daily. Work-up by her previous physicians included the following: A skull roentgenogram which revealed no er:largement of the sella turcica; an cndometrial biopsy which produced no tissue; pituitary gonadotropins which were below 6 mouse uterine units for 24 hours; and urinary 17-ketosteroid c,scretion of 4 mg. in 24 hours. On physical examin.ltion, the patient had a normal feminine configuration. There was no hirsutism or acne. The breasts were well drvelopcd. The external :cnitals were norma and the clitoris was not enl.uged. The uterine fundus was slightly smaller than normal. The ovaries were not enlarged. Endocrine and infertility evaluation reflected a moderate deficiency in estrogen production. There was abundant, clear cervical mucus which yielded a 4+ arborization rraction on drying. A vaginal smear revealed 88 per cent intermediate cells and 12 per cttnt superficial cells. Endometrial biopsy with a suction curctte was productive only of scanty fragments of hypotrophic cndomctrium. Twent>-four hour 17-ketosteroid excretion was 9.2 mg. FSH (gonadotropin) excretion was between 6 and 50 mouse uterine units in 24 hours. Prednisone was giLen in a dosage of 5 mg. twice daily starting on June 11, 1966. The patient had an ovulatory period on July 5, 1966, and again on Aug. 2, 1966, as evidenced by a 14 day rise in basal temperature preceding the menstrual flow. She had intermittent staining but no ovulation in September. 1966. A 10 hour postcoital test revealed 0 to 2 sperm per high-power field in 2: favorable type of mucus. A semen analysis corroborated a male factor, there being only 8 million spermatozoa per CUbit centimeter with a total of 2 C.C. of semen. Comment These ovulation
4
cases
show
can be a sequel
that
prolonged
to the
oral
ancontra-
1068
Dodek
and Kotz
ceptives. In addition to these, in the past year we have seen 3 other infertile patients who have had anovulation or infrequent ovulation following cessation of oral contraceptives, but evaluations of these patients are incomplete at this time so that detailed case reports are not included here. Whitelaw, Nola, and Kalmanl reported 17 cases of anovulation following the oral contraceptives and mentioned that personal communications with other gynecologists led them to believe that there are many patients with amenorrhea of three months or more, or marked irregularity of their menstrual cycles and infertility following discontinuation of oral contraceptive therapy. We have recently answered a question from the International Obstetrics-Gynecology Correspondence Letter commenting on the management of anovulation following the use of oral contraceptives.” It is likely that this syndrome is being encountered by many physicians throughout the world, although the exact incidence is unknown. What is the endocrinopathy involved? The action of the birth control pills in controlling conception is suppression of ovulation. The site of action is presumably those centers within the hypothalamus which are concerned with gonadotropin release, and particularly those centers which cause the cyclic release of luteinizing hormone.4 The oral contraceptives also cause changes in the endometrium and in the cervical mucus which interfere with successful pregnancy, but there is fairly general agreement that the central feedback suppression of the cyclic centers is the paramount mode of action. It is therefore logical to assume that in certain patients this effect on the hypothalamus is not immediately reversible and the result is protracted anovulation. Gaul’ and Maqueo’ reported that significant numbers of women showed no elevation in their excretion levels of pregnanediol or failed to have evidence of ovulation as determined by premenstrual endometrial biopsies during the first 3 months after cessation of sequential oral contraceptive therapy. Whitelaw, Nola, and Kalman’ also expressed the opinion that
August 15, 1967 Am. J. Obst. & Gynrc.
interference with gonadotropin release was operative in this group of patients. Three of our patients responded promptly to the administration of preclnisone (5 mg. twice daily) with the appearance of ovulatory cycles. Therefore, the question can be raised as to whether a condition of androgenic adrenal hyperactivity exists. Previous studies on the effects of Enovid on adrenal function indicates that there is an increase in the plasma concentration of tortisol and a significant decrease in the metabolic clearance of cortisol. Both of these changes can be attributed to an increase in transcortin, the cortisol-binding globulin, as a result of the estrogenic activity of the oral contraceptives. However, the production rate of cortisol is unaffected.7 There is also no evidence of an increase in the production of dehydroepiandrosterone, A4 androstenedione, or 1 lp-hydrosyandrostenedione as a result of oral contraceptive therapy. Increases in the production of these carbon-l 9 compounds should be reflected in the urine by an increase in neutral 17-ketosteroid excretion. Such increments ha\:e not been demonstrated.8 It is conceivable that an increase in adrenal production of testosterone could be responsible for compromise in cyclic hypothalamic activity. We are unaware of any studies measuring plasma or urinary testosterone levels or testosterone production rates of patients taking oral contraceptives. It is difficult to postulate an increase in adrenal testosterone production without a concomitant rise in the output of the other weaker carbon- 19 compounds. One is not justified in concluding that a patient has adrenal hyperfunction becaust. there is a response to corticosteroid therapy.” There are other theoretical means by which a glucocorticoid may be active in producing ovulation besides the effect of suppressing ACTH production. Sohval and Soffer’” first demonstrated an increase in gonadotropin excretion following exogenous cortisone. Barlow] * has reported an enhancement of estrogen production during the follicular phase of the cycle following dexamethasone administration. Therefore, the effect of the
Volume Number
98 8
prednisone in our cases is very possibly directly on those hypothalamic centers concerned with gonadotropin release. The management of patients with menstrual dysfunction following discontinuation of the oral contraceptives should begin if there has been amenorrhea or evidence of anovulation of 3 or more months. Following the complete history and physical examination, the initial step should be an assessment of endogenous estrogen production. This includes a vaginal smear from which the percentage of cornified cells can be determined. The cervical mucus is examined with reference to the amount, viscosity, spinnbarkheit, and arborization potential. A sample of endometrium can be obtained by a suction currette for microscopic evaluation of the degree of proliferation. The quality of estrogen priming of the endometrium can be further evaluated by the presence or absence of withdrawal bleeding following administration of Provera, 10 mg., daily for 5 days. Evidence of a high level of endogenous estrogen production reflects a less profound hypothalamic dysfunction and probably indicates that induction of ovulation will occur more readily with therapy. The presence of a high level of endogenous estrogen is also the best test we have that the anterior pituitary is producing gonadotropin. In the presence of estrogen deficiency a skull film with views of the sella turcica is obtained. The measurement of urinary gonadotropin by the mouse uterine weight method will not be of much aid in management of the patient, because in all likelihood, the result will be either in the normal or low range. If the periods had been regular before taking the oral contraceptives, one would hardly expect ovarian failure with resultant high gonadotropin titers in this group of patients. The 24 hour urinary 17-ketosteroid excretion is also determined. In all 4 of our patients these levels were within the normal female range. It has been our practice, when there has been short term anovulation, especially with evidence of endogenous estrogen production, to prescribe prednisone, 5 mg., twice daily. With this treatment the return of ovulatory
Anovulation
after
oral
contraceptives
1069
cycles many times occurs quite promptly. For this reason the initial therapy in those patients with anovulation following cessation of the oral contraceptive was prednisone. Prednisone has the advantage of ease of administration and virtual lack of side effects or complications in this low dosage. In addition, if successful, there is a return of the patient’s own cyclic gonadotropin stimulation and, therefore, elimination of the problems of ovarian ,:yst development or multiple pregnancies which may occur with the use of Clomid” or Pergonal. If, after 3 months of therapy, there is no response to prednisone, the use of Clomid or Pergonal is then indicated. Whitelawl? reported excellent results with Clomid (16 of 20 patients with iatrogenic amenorrhea responded to therapy) and our patient (Case 3) responded promptly to Pergonal and chorionic gonadotropin. The fact that the patients in our series and that of Whitelaw ovulated readily with therapy indicates that anovulation following the oral contraceptives in many cases is a relatively mild endocrinopathy and allows a favorable prognosis to be rendered when the patient is first seen. This is especially true when there is evidence of good endogenous estrogen production. However, there is apparently a small number of patients with this syndrome displaying marked estrogen deficiency, who are refractory to “any type of therapy.“l We would certainly be anxious to see published reports of such patients who are unable to respond to repeated courses of exogenous gonadotropin, because this would suggest an ovarian rather than a central abnormality. We agree with Whitelaw, Nola, and Kalman1 that patients should be cautioned about the possibility of subsequent anovulation and infertility before the oral contraceptives are prescribed. There is al$o only the flimsiest of evidence that oral contraceptives are capable of improving the chances of conception in the infertile patient.’ Therefore, it is urged that they not be used empirically in the management of infertility, at least until all ‘Clomiphene Cincinnati. Ohio.
citratr.
The
Wm.
S.
Merrcll
Company.
1070
Dodek
and
Kotz
avenues of diagnosis and therapy have been exhausted. We are not aware of any means of predicting which patients will develop anovulatory problems after using the oral
contraceptives, but it would seem prudent to avoid dispensing them to patients with a history of prolonged episodes of amenorrhea.
REFERENCES
1.
Whitelaw, J. J., Nola, V. F.. and Kalman. C. F.: J. A. M. A. 195: 780, 1966. 2. Katz, H. L.. and Dodek, 0. I.: M. Ann. District of Columbia 35: 255, 1966. 3. Katz, H. L., and Dodek, 0. I.: Collected letters of International Obstetrics-Gynecology Correspondence Letter. In press, 1966. 4. Taymor, M. I,.: J. Clin. Endocrinol. 24: 803, 1964. 5. Gaul, C.: Excerpta med., Abst. 372. October. 1965. 6. Maqueo, T. M.: Excerpta med.. Abst. 375, October. 1965. 7. Dodek, 0. I., Sagre, E. J., and Klaiber. E. & GYNEC. 93: 173. 196.5. I.: AM. J. OBST.
8.
9. 10. 1 1. 12.
Drill, V. A.: Oral Contraceptives, New York. 1966, McGraw-Hill Book Company, Inc., p. l-11. Katz, H. L., and Herrmann, W.: Fertil. KSteril. 12: 271, 1961. Sohval, A. R., and Soffer, L. J.: J. Clin. Endocrinol. 11: 677, 1951. Barlow, J. J.: J. Clin. Endocrinol. 24: 586. 1965. Whitelaw, J. J.: Fertil. & Steril. 17: .X&l. 1966. 8218 Wisconsin Avenue Bethesda, Maryland 20014
following the
oral contraceptives OSCAR
I.
HERBERT Bethesda,
DODEK, L.
JR.:
KOTZ,
M.D.
M.D.,
F.A.C.O.G.
Maryland
Four cases of anovulation following use of oral contraceptives are presented, outlining the diagnostic evaluation and therapy. The mechanism for the failure of reappearance of ovulation is felt to be prolonged dysfunction of hypothalamic centers concerned with cyclic gonadotropin release. Prednisone, 5 mg. twice daily for 3 months, is suggested as initial therapy. Zf return of ovulation does not follow prednisone administration, use of Clomid or Pergonal is indicated. The favorable response of these patients to therapy suggests that, in many instances, the anovulation following the oral contraceptives is a relatively mild endocrinopathy.
DYSFUNCTION
MENSTRUAL
Menarche was at age 12. Her periods were always regular, occurring every 29 days, lasting 5 to 6 days, and accompanied by premenstrual molimina and dysmenorrhea. Following cessation of oral contraceptive therapy, the menses were grossly irregular. Between February, 1964, and her initial visit in September, 1964, the patient had two episodes of very prolonged cycles during which the diagnosis of pregnancy was entertained but never established. On initial physical examination the patient displayed a normal feminine configuration. There was mild facial acne. The hair distribution was not unusual and the breasts were well developed. Pelvic examination revealed normal external genitals with a normal clitoris. The uterus and adnexa were palpable and normal. Infertility and endocrine evaluation indicated adequate endogenous estrogen, as evidenced by excellent arborization of clear, elastic cervical mucus, and by a withdrawal menstrual flow following oral administration of 10 mg. of Provera” daily for 5 days. Basal body temperature charts between September, 1964, and January, 1965, confirmed the absence of ovulation. Skull roentgenograms revealed no abnormality of the sella turcica. A 24 hour urinary excretion of 17-ketosteroids was 12.3 mg. and the protein-bound iodine was 3.5 pg per cent. A 10 hour postcoital examination of the
fOl-
lowing use of the oral contraceptives is a disturbing syndrome which has now made its appearance in clinical practice.1’2 The problem occurs at a time when the patient has decided to increase her family and infertility secondary to anovulation or irregular ovulation is a source of great anxiety. The purpose of this paper is to call further attention to this problem and to outline the management of four such patients from our private practice. Two of the patients were described in a previous comment on the relationship between oral contraceptives and infertility and we now are able to report the menstrual course of these patients following successful pregnancy.’ Case
reports
Case 1. A 22-year-old, gravida 0, Caucasian woman was referred on Sept. 29, 1964, for infertility evaluation. She had been placed on Enovid” (dosage unknown) as an oral contraceptive at the time of her marriage in June, 1963. The contraceptive pills were discontinued in Frbruary, 1964. From the Department of Obstetrics Gynecology, Washington Hospital Center.
and
*Norethynodrel and mestranol, G. D. Searle d Company, Chicago, Illinois.
‘6n-methyl-l7-acetoxyprogesterone, Kalamazoo, Michigan.
1065
The
Upjohn
Company,
1066
Dodek
and
Kotz
Am.
cervical tnucus revc,aled 2 to 5 progressively motile sperm per high-power field, and semen analysis was normal. A Ruhin carbon dioxide tubal insufflation indicated tubal patency by auscultation, thermograph, and prompt bilateral shoulder pain. I,-thyroxinc therapy, 0.1 mg. per day, !~as initiated on Dee. 24, 1964. The patient remained anovulatoty until prcdnisone,” 5 mg. twice daily, her first ovulatory was s:tartcd Jan. 29, 1965, menses occurring on Frh. 25, 1965. She was conovulatory tinued on prcdnisonc an d also had cycles in March, April, and May as evidenced by a biphasic basal I)ody rctttpcraturc curve and cndometrial biopsy. The patient conceived in rarly June, 1965, and had a normal vaginal delivery of a 5 pound, 10 otmcc fcmalr in good condition on Jan. 14, 1966. Prednisone had brrn continued through the fourteenth week of pregnancy. The patient’s II~CIIWS rcturttrd without thcrapy within 2 months of deli\rery attd were fairly regular, although ttot of the precise regularity that was present bcforc her marriage. She conceived again in July, 1966, and is now in the second crimrstcr of an uncomplicated prcgttancy. Case 2. A 23-year-old, gravida 0, Caucasian woman was rcfcrred on March 29, 1965, for an infertility evaluation. She had used Enovid, 5 for contraception from the time tng. cyclically, of her marriage in 1962 until July, 1964. The menarchc was at age 13 and the periods were always regular, occurring every 30 days, lasting 5 days. and associated with premenstrual tnolimina and dysmenorrhea. Following cessation of the Enovid her periods became grossly irregular, attd the patient had complete amrnorrhea from Novemh(br, 1964, until hrr first visit in March, 1965. She also romplaintd of facial arne and slight ditninution of hrrast size since discontinuing oral contraception. On physical examination the patient displayed a normal femininr c,onfiguration. There \vas marked facial acne. The hair distribution was normal and the breasts wcrc well developed. recavalrd normal external Pelvic examination genitals and the clitoris was not enalrged. Tht, uterus and adnexa \verc normal. Enhocrinc and infertility evaluation indicated adequate cndogrnous estrogen, as evidenced by arborization of the cervical murus and by a withdrawal flow following oral administration “A’-hydrocortisone,
West-Ward,
Inc.
.4ugu\t J. Obrt.
15. IYtii & (;ywr.
of Provera, 10 mg. daily for 5 days. Thr patie-nt had measured her hasal body tcmpcraturr front Jan. 18, 3965, through March 29. 19G5, \\hilc she was amenorrheic, and thrrc \vas no cvidcrtc~~~ of a biphasic curve. Skull rorntgcnogratns revcalcd no abnormality of the sclla turrira. .4 24 hour urinary rscrrtion of 17-kctostcroids \vas I -I.(i mg. and the prntcin-bound iodinr w;ts 5.1 ,A!: p;‘r crnt. A 10 hour postcoital examination rc,vrtalrd inttutttcrablr progressively niotilca yp’rnt p-1 high-power tir>ld and a sprrm cr,unt contirmcd the. absenrc, of a male factor. ?‘lt(, Rubin tc’\i \VBS diagnostic of tubal patcmcy. ‘I’h,, patient was started on prednisonc*. 5 1112, twiccx daily, on May 10, 1965. and had an ovtrlator); plbriod on June 16, 1965. as irtdic.atcd by a biphasic basal body temprraturcx cur\-tx. Shr ronccivtxd in ~trly July, 1965. and way drlivtsrcd \ragittallv of a ti pound, 8 ounce frmalc on March ‘1.5, 19ti6, Tvithout complication. PAnisonr had brcn taken through the fourtcc~tttlt \VWk of pregnancy. Her mcnscs rrturnc.d promptly following dclivcry and have brtxn r,‘gular. An intrauterine d&cc has been 1tht.d fat conlraccption. Case 3. A 23-yrar-old, gravida 0, woman was rcfrrrcd for an infrrtility evaluation on June 6. 1966. ‘I‘hc, patient hqan using oral contraq~tivct.q at the timr of hrr nt:trriagr in JUIW. 1963, and took them until Jan. IO, 1966. in routinc cyclic fashion. She took Enovid f 10 111g. ) . Enovid (5 mg.), or Ortho-Novum” j2 my.) during this time. The rhoicy of cotttracc’ptivc.s dcpendcd on thr sampl(>s availahlc in thr of& of a physician mcrnbrr of thr family. The patirnt had no sidt, rffects from an) of them. She had atnrnorrhra from thr timr shr stopped (hf. pills until her initial viGt itt Junr. I otiti. Menarchr occurred at agr 12. Hrr periods had always occurred monthly and wrrr accotttpanicad by premenstrual tnolimina. She had nrvct previously skipped a monthly flow. On initial physical examination the patittnt had a normal feminine confqtration. There w’as no hirsutism or acne and thr breasts were wc,ll drvrlopcd. The rxtrrnal genitals w?rr normal :tttd the clitoris w;ts not enlarged. The uterine frmdus cons antrflrxr~d. firm, qmntctrical? ntobilr. and slightly smallrr than normal. Thr ovaries wrrr not enlarged.
Anovulation
Endocrine and infertility evaluation reflected ;L low level of endogenous estrogen production. There was scant and viscid cervical mucus. A scraping obtained from the midlateral vaginal wall rc,vcalrd 95 per rent intermediate cells and 5 per cent superficial ~11s. A thorough exploration of the endometrial cavity with a suction curettc produced only scant fragments of hypotrophic endometrium. Provera, 10 mg. daily for 5 days, \vas prescribed in March, 1966, with only one episode of slight staining following withdrawal. Protein-bound iodine in March, 1966, was 3.7 pg per cent. The patient had been given triiodothyronine, 25 pg daily, and was taking this medication when first seen. Twenty-four hour urinary 17-ketossteroid excretion was 11.0 mg. A skull rentgenogram showed no enlargement of the sella turcica. Urinary excretion of FSH (gonadotropins) was between 6 and 16 mouse uterine units in 24 hours. Prrdnisonc, 5 mg. twice daily, was administered from June G, 1966, through Aug. 10, 1966, without effect on the basal temperature cute or the cervical mucus. From Aug. 10, 1966, through Aug. 20, 1966, Pergonal” was given in a dosage of 75 I.U. intramuscularly t\\ic.c, daily. On Aug. 19, 1966, a 10 hour postcoital examination of the cervical mucus revcalrd a profuse amount of clear, glary, elastic mucus. Thrrc were 5 to 10 sperm in each highpotvcr field, of which 40 per cent were proRrrGvcly motile,. The patient was given 5,000 units of APLt intramuscularly every 12 hours for four doses, the first being given simultaneously with the last injection of Pergonal, The couple was instructed to have coitus nightly. The basal tcmpcraturc rose on Aug. 23, 1966, and remained elevated. An immunologic pregnancy tct was positive on Sept. 20, 1966. The patient i< now in the first trimester of her pregnancy. Case 4. A 26-year-old, gravida 0, Caucasian woman was refcrrrd on June 10, 1966, for an infrrtility evaluation. She had her menarche at aqc 15, and had menstrual dysfunction before her marriage with the following general patterns: Periods would come monthly for 2 months, but during the third month the patient Lvould have only an episode of staining. During “Human menopausal qonadotropin, Cuttrr Laboratories, Rcrkelry, California. This patient was included in a Pergonat study conducted by Dr. Nathan Kasr. Associate Professor. Ob\tctrics and Gynecology, Yale University Scbont of Meditine. uho supel\,ised the therapy. Neu
tHumari York,
chorionic Nrw York.
gvnadotropin.
Aycrst
Labolator
ies,
after oral contraceptives
1067
a typical year there would be 6 to 8 periods accompanied by premenstrual molimina. She began taking Ortho-Novum, 2 mg., for oral contraception at the time of her marriage in October, 1964. She tclok the pills in the standard cyclic dosage until thv end of June, 1965. The patient had no spontaneous menses from that time until her initial visit. However, she had staining every few weeks for the entire year. In December, 1965, there had been withdrawal flow following five days of Provera, 10 mg. daily. Work-up by her previous physicians included the following: A skull roentgenogram which revealed no er:largement of the sella turcica; an cndometrial biopsy which produced no tissue; pituitary gonadotropins which were below 6 mouse uterine units for 24 hours; and urinary 17-ketosteroid c,scretion of 4 mg. in 24 hours. On physical examin.ltion, the patient had a normal feminine configuration. There was no hirsutism or acne. The breasts were well drvelopcd. The external :cnitals were norma and the clitoris was not enl.uged. The uterine fundus was slightly smaller than normal. The ovaries were not enlarged. Endocrine and infertility evaluation reflected a moderate deficiency in estrogen production. There was abundant, clear cervical mucus which yielded a 4+ arborization rraction on drying. A vaginal smear revealed 88 per cent intermediate cells and 12 per cttnt superficial cells. Endometrial biopsy with a suction curctte was productive only of scanty fragments of hypotrophic cndomctrium. Twent>-four hour 17-ketosteroid excretion was 9.2 mg. FSH (gonadotropin) excretion was between 6 and 50 mouse uterine units in 24 hours. Prednisone was giLen in a dosage of 5 mg. twice daily starting on June 11, 1966. The patient had an ovulatory period on July 5, 1966, and again on Aug. 2, 1966, as evidenced by a 14 day rise in basal temperature preceding the menstrual flow. She had intermittent staining but no ovulation in September. 1966. A 10 hour postcoital test revealed 0 to 2 sperm per high-power field in 2: favorable type of mucus. A semen analysis corroborated a male factor, there being only 8 million spermatozoa per CUbit centimeter with a total of 2 C.C. of semen. Comment These ovulation
4
cases
show
can be a sequel
that
prolonged
to the
oral
ancontra-
1068
Dodek
and Kotz
ceptives. In addition to these, in the past year we have seen 3 other infertile patients who have had anovulation or infrequent ovulation following cessation of oral contraceptives, but evaluations of these patients are incomplete at this time so that detailed case reports are not included here. Whitelaw, Nola, and Kalmanl reported 17 cases of anovulation following the oral contraceptives and mentioned that personal communications with other gynecologists led them to believe that there are many patients with amenorrhea of three months or more, or marked irregularity of their menstrual cycles and infertility following discontinuation of oral contraceptive therapy. We have recently answered a question from the International Obstetrics-Gynecology Correspondence Letter commenting on the management of anovulation following the use of oral contraceptives.” It is likely that this syndrome is being encountered by many physicians throughout the world, although the exact incidence is unknown. What is the endocrinopathy involved? The action of the birth control pills in controlling conception is suppression of ovulation. The site of action is presumably those centers within the hypothalamus which are concerned with gonadotropin release, and particularly those centers which cause the cyclic release of luteinizing hormone.4 The oral contraceptives also cause changes in the endometrium and in the cervical mucus which interfere with successful pregnancy, but there is fairly general agreement that the central feedback suppression of the cyclic centers is the paramount mode of action. It is therefore logical to assume that in certain patients this effect on the hypothalamus is not immediately reversible and the result is protracted anovulation. Gaul’ and Maqueo’ reported that significant numbers of women showed no elevation in their excretion levels of pregnanediol or failed to have evidence of ovulation as determined by premenstrual endometrial biopsies during the first 3 months after cessation of sequential oral contraceptive therapy. Whitelaw, Nola, and Kalman’ also expressed the opinion that
August 15, 1967 Am. J. Obst. & Gynrc.
interference with gonadotropin release was operative in this group of patients. Three of our patients responded promptly to the administration of preclnisone (5 mg. twice daily) with the appearance of ovulatory cycles. Therefore, the question can be raised as to whether a condition of androgenic adrenal hyperactivity exists. Previous studies on the effects of Enovid on adrenal function indicates that there is an increase in the plasma concentration of tortisol and a significant decrease in the metabolic clearance of cortisol. Both of these changes can be attributed to an increase in transcortin, the cortisol-binding globulin, as a result of the estrogenic activity of the oral contraceptives. However, the production rate of cortisol is unaffected.7 There is also no evidence of an increase in the production of dehydroepiandrosterone, A4 androstenedione, or 1 lp-hydrosyandrostenedione as a result of oral contraceptive therapy. Increases in the production of these carbon-l 9 compounds should be reflected in the urine by an increase in neutral 17-ketosteroid excretion. Such increments ha\:e not been demonstrated.8 It is conceivable that an increase in adrenal production of testosterone could be responsible for compromise in cyclic hypothalamic activity. We are unaware of any studies measuring plasma or urinary testosterone levels or testosterone production rates of patients taking oral contraceptives. It is difficult to postulate an increase in adrenal testosterone production without a concomitant rise in the output of the other weaker carbon- 19 compounds. One is not justified in concluding that a patient has adrenal hyperfunction becaust. there is a response to corticosteroid therapy.” There are other theoretical means by which a glucocorticoid may be active in producing ovulation besides the effect of suppressing ACTH production. Sohval and Soffer’” first demonstrated an increase in gonadotropin excretion following exogenous cortisone. Barlow] * has reported an enhancement of estrogen production during the follicular phase of the cycle following dexamethasone administration. Therefore, the effect of the
Volume Number
98 8
prednisone in our cases is very possibly directly on those hypothalamic centers concerned with gonadotropin release. The management of patients with menstrual dysfunction following discontinuation of the oral contraceptives should begin if there has been amenorrhea or evidence of anovulation of 3 or more months. Following the complete history and physical examination, the initial step should be an assessment of endogenous estrogen production. This includes a vaginal smear from which the percentage of cornified cells can be determined. The cervical mucus is examined with reference to the amount, viscosity, spinnbarkheit, and arborization potential. A sample of endometrium can be obtained by a suction currette for microscopic evaluation of the degree of proliferation. The quality of estrogen priming of the endometrium can be further evaluated by the presence or absence of withdrawal bleeding following administration of Provera, 10 mg., daily for 5 days. Evidence of a high level of endogenous estrogen production reflects a less profound hypothalamic dysfunction and probably indicates that induction of ovulation will occur more readily with therapy. The presence of a high level of endogenous estrogen is also the best test we have that the anterior pituitary is producing gonadotropin. In the presence of estrogen deficiency a skull film with views of the sella turcica is obtained. The measurement of urinary gonadotropin by the mouse uterine weight method will not be of much aid in management of the patient, because in all likelihood, the result will be either in the normal or low range. If the periods had been regular before taking the oral contraceptives, one would hardly expect ovarian failure with resultant high gonadotropin titers in this group of patients. The 24 hour urinary 17-ketosteroid excretion is also determined. In all 4 of our patients these levels were within the normal female range. It has been our practice, when there has been short term anovulation, especially with evidence of endogenous estrogen production, to prescribe prednisone, 5 mg., twice daily. With this treatment the return of ovulatory
Anovulation
after
oral
contraceptives
1069
cycles many times occurs quite promptly. For this reason the initial therapy in those patients with anovulation following cessation of the oral contraceptive was prednisone. Prednisone has the advantage of ease of administration and virtual lack of side effects or complications in this low dosage. In addition, if successful, there is a return of the patient’s own cyclic gonadotropin stimulation and, therefore, elimination of the problems of ovarian ,:yst development or multiple pregnancies which may occur with the use of Clomid” or Pergonal. If, after 3 months of therapy, there is no response to prednisone, the use of Clomid or Pergonal is then indicated. Whitelawl? reported excellent results with Clomid (16 of 20 patients with iatrogenic amenorrhea responded to therapy) and our patient (Case 3) responded promptly to Pergonal and chorionic gonadotropin. The fact that the patients in our series and that of Whitelaw ovulated readily with therapy indicates that anovulation following the oral contraceptives in many cases is a relatively mild endocrinopathy and allows a favorable prognosis to be rendered when the patient is first seen. This is especially true when there is evidence of good endogenous estrogen production. However, there is apparently a small number of patients with this syndrome displaying marked estrogen deficiency, who are refractory to “any type of therapy.“l We would certainly be anxious to see published reports of such patients who are unable to respond to repeated courses of exogenous gonadotropin, because this would suggest an ovarian rather than a central abnormality. We agree with Whitelaw, Nola, and Kalman1 that patients should be cautioned about the possibility of subsequent anovulation and infertility before the oral contraceptives are prescribed. There is al$o only the flimsiest of evidence that oral contraceptives are capable of improving the chances of conception in the infertile patient.’ Therefore, it is urged that they not be used empirically in the management of infertility, at least until all ‘Clomiphene Cincinnati. Ohio.
citratr.
The
Wm.
S.
Merrcll
Company.
1070
Dodek
and
Kotz
avenues of diagnosis and therapy have been exhausted. We are not aware of any means of predicting which patients will develop anovulatory problems after using the oral
contraceptives, but it would seem prudent to avoid dispensing them to patients with a history of prolonged episodes of amenorrhea.
REFERENCES
1.
Whitelaw, J. J., Nola, V. F.. and Kalman. C. F.: J. A. M. A. 195: 780, 1966. 2. Katz, H. L.. and Dodek, 0. I.: M. Ann. District of Columbia 35: 255, 1966. 3. Katz, H. L., and Dodek, 0. I.: Collected letters of International Obstetrics-Gynecology Correspondence Letter. In press, 1966. 4. Taymor, M. I,.: J. Clin. Endocrinol. 24: 803, 1964. 5. Gaul, C.: Excerpta med., Abst. 372. October. 1965. 6. Maqueo, T. M.: Excerpta med.. Abst. 375, October. 1965. 7. Dodek, 0. I., Sagre, E. J., and Klaiber. E. & GYNEC. 93: 173. 196.5. I.: AM. J. OBST.
8.
9. 10. 1 1. 12.
Drill, V. A.: Oral Contraceptives, New York. 1966, McGraw-Hill Book Company, Inc., p. l-11. Katz, H. L., and Herrmann, W.: Fertil. KSteril. 12: 271, 1961. Sohval, A. R., and Soffer, L. J.: J. Clin. Endocrinol. 11: 677, 1951. Barlow, J. J.: J. Clin. Endocrinol. 24: 586. 1965. Whitelaw, J. J.: Fertil. & Steril. 17: .X&l. 1966. 8218 Wisconsin Avenue Bethesda, Maryland 20014