Chapter 47

Amenorrhea

Liuska Pesce and Donald Zimmerman

Objectives
1. To recognize hypergonadotropic hypogonadism as part of the differential
diagnosis of delayed puberty
2. To recognize premature ovarian failure as a cause of hypergonadrotropic hypog-
onadism
3. To recognize chemotherapy and cancer treatment modalities as etiologies of
gonadal failure
4. To understand that it is hard to predict which patients will resume normal ovarian
function after chemotherapy-induced failure

Case Presentation
A 16½-year-old girl presented with amenorrhea. She had experienced thelarche and
pubarche at 10 years of age, followed by one episode of vaginal bleeding at 12 years
old. At that time, she was diagnosed with rhabdomyosarcoma of the right hand.
She was prescribed cyclophosphamide, vincristine, and dactinomycin. Three years
later, rhabdomyosarcoma appeared in her right breast. Another course of treatment
with chemotherapy was administered, which included cyclophosphamide, mesna,
and tirapazamine.
She had been in remission from rhabdomyosarcoma for 1 year when she pre-
sented with amenorrhea. She had only had one menstrual period.
On physical examination, height was 151.7 cm (3rd to 10th percentiles), and
weight was 53 kg (50th percentile). Breasts and pubic hair were in Tanner stage V.
Her right breast showed a scar from tumor resection and later breast reconstruction.
Her right hand was mildly atrophic and also had a scar from tumor resection. The
rest of her physical exam was normal.

L. Pesce
Fellow in Pediatric Endocrinology Children’s Memorial Hospital and Northwestern University’s,
Feinberg School of Medicine

T.F. Davies (ed.), A Case-Based Guide to Clinical Endocrinology, 433


C Humana Press, Totowa, NJ 2008
434 L. Pesce, D. Zimmerman

Serum follicle-stimulating hormone (FSH) measured 66.3 mIU/mL (normal

range: 1.5–9); luteinizing hormone (LH) measured 27.4 mIU/mL (normal range:
0.02–12); and estradiol measured 29 pg/mL (normal range for age: 40–410).
There were normal circulating levels of thyroid-stimulating hormone (TSH)
(0.911 mIU/mL) and prolactin (7.47 ng/mL).

How the Diagnosis Was Made

The diagnosis was hypergonadotropic hypogonadism secondary to chemotherapy-
induced ovarian failure. Delayed puberty is defined as lack of onset of pubertal signs
by the age of 13 years in girls and 14 years in boys, or as the lack of normal pro-
gression of puberty. Evaluation may be indicated if more than 5 years have elapsed
between the first signs of puberty and menarche in girls, or completion of genital
growth in boys [1].
Delayed puberty may be idiopathic or familial or due to a number of conditions
resulting in undernutrition. However, absence or lack of progression of puberty may
also be due to impaired gonadotropin secretion or due to gonadal failure [2].
The first approach in evaluating patients with delayed or lack of progression of
puberty is to determine gonadotropin status. Elevated levels of gonadotropins indi-
cate gonadal failure (hypergonadotropic hypogonadism).
Hypergonadotropic hypogonadism may be secondary to genetic, autoimmune,
and infectious conditions, but also secondary to radiotherapy and chemotherapy
[2, 3].
Advances in the management of cancer, with cytotoxic chemotherapy and
radiotherapy, have improved cure rates of many young patients. For many of
the malignancies affecting children and adolescents, survival rates exceed 60% and
the mortality rate for childhood leukemia has decreased by more than 70% in the
developed world (3–5). However, treatment is associated with significant morbidity
and alterations in gonadal function are among the most common long-term effects
of therapy [6].
Germinal epithelial damage resulting in oligospermia and azoospermia have long
been recognized in the male. Although the ovary appears to be less vulnerable than
the testis, ovarian failure is not uncommon following cytotoxic treatments [6], with
reduced amounts of follicles and ovarian atrophy [5]. Since many of these patients
are young, with expectations of normal reproductive life span, premature ovarian
failure can impact their self-esteem and quality of life [5].
The effects of gonadotoxic effects of chemotherapy were first reported in patients
treated with busulfan for chronic myeloid leukemia [6]. However, premature ovar-
ian failure has been described with other drugs. Most of the available data are on
patients treated for leukemia, lymphoma, and breast cancer. Most of the information
available is on cyclophosphamide, methotrexate, and 5-fluorouracil [4].
The gonadal damage depends on the agent used, the dose, and the age of the
patient. Younger patients appear to tolerate higher doses, and ovarian function starts
again once treatment is suspended. The latent period before the reappearance of
47 Amenorrhea 435

normal menstruation is widely variable [4]. It is presumed than younger women are
more resistant probably because of larger follicle stores prior to treatment [5].
Gonadal failure following chemotherapy in patients younger than 20 years has
been estimated to be 13%, 50% in women 20 to 30 years old, and 100% in patients
older than 30 years. Also, it has been noted than girls treated prior to menarche
fail to start menarche while on therapy, but are able to have menarche shortly after
cessation of the cytotoxic agents, while most of the girls who are started on treatment
after menarche develop secondary amenorrhea [4].
Alkylating agents have been found impose the highest risk of ovarian failure,
with cyclophosphamide having an odds ratio (OR) of 1.77 [5].
Even if women have normal cycles immediately following cessation of therapy,
they may have premature menopause (42% may enter menopause by 31 years of
age compared to 5% of controls) [6]. On the other hand, amenorrhea following
chemotherapy does not necessarily imply permanent ovarian failure. A proportion of
women may recover ovarian function, being able to have normal menses and fertility
[5, 6]. Currently, there are no indicators allowing identification of this subgroup
of patients, but it is more likely to occur in younger patients. However, inhibin A
and B are being evaluated as possible markers of gonadotoxicity with promising
results [3].
Gonadotropin-releasing hormone administered as adjuvant therapy together with
chemotherapy, appears to protect adolescent girls from chemotherapy-associated
gonadotoxicity manifested as hypergonadotropic amenorrhea. It also appears to pro-
long the fertility window by almost 10 years [3]. However, other studies have not
support this beneficial effect [5].

References
1. Lee PA and Hook CP. Puberty and its disorders in Lifshitz F (ed) Pediatric Endocrinology 5th
edition. New York Informa Health Care 2006;273–303.
2. Hickey M, Balen A. Menstrual disorders in adolescence: investigation and management. Hum
Reprod Update 2003;9(5):493–504.
3. Blumenfeld Z. Gynaecologic concerns for young women exposed to gonadotoxic chemother-
apy. Curr Opin Obstet Gynecol 2003;15(5):359–70.
4. Lo Presti A. Ruvolo G, Gancitano RA, Cittadini E. Ovarian function following radiation and
chemotherapy for cancer. Eur J Obstet Gynecol Reprod Biol 2004;113 Suppl 1:S33–40.
5. Meirow D, Nugent D. The effects of radiotherapy and chemotherapy on female reproduction.
Hum Reprod Update 2001;7(6):535–43.
6. Howell S, Shalet S. Gonadal damage from chemotherapy and radiotherapy. Endocrinol Metab
Clin North Am 1998;27(4):927–43.

Multiple-Choice Questions

1. A 17-year-old girl presents to the clinic for the evaluation of primary amenor-
rhea. Which would be an important aspect of her clinical history?

A. History of leukemia during infancy

B. Short stature
436 L. Pesce, D. Zimmerman

C. History of delayed puberty in the family

D. All of the above
E. None of the above
Answer: D.
2. In the above patient, which of the following labs results would make you consider
the diagnosis of ovarian failure?
A. FSH of 60 IU/L (normal 0.33–10.54)
B. Estradiol of 100 pg/ml (normal 40–410)
C. LH of < 0.2 IU/L (normal 0.69–7.15)
D. All of the above
E. None of the above
Answer: A.
3. Which of the following could explain premature ovarian failure in this 17-year-
old girl?
A. Prolactinoma
B. Oophoritis
C. Chemotherapy
D. Hypogonadal hypogonadism
E. All of the above
F. B and C
G. None of the above
H. A and D
Answer: F.
4. Which of the following chemotherapeutic agents have been highly associated
with premature ovarian failure?
A. Antibiotics
B. Antimetabolites
C. Plant alkaloids
D. Alkylating agents
Answer: D.
5. Which of the following patients could potentially have the worst fertility prog-
nosis based on the current information we have on chemotherapy-induced pre-
mature ovarian failure?
A. A 7 years old currently being treated with cyclophosphamide
B. A 14 years old who had menarche at age 12 years, who completed treatment
with cyclophosphamide three months ago, with amenorrhea for the last year
C. A 30 year old female who completed chemotherapy with cyclophosphamide
3 months ago and currently has normal menstrual cycles.
D. A and B
Answer: C.