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Primary Ovarian
Insufficiency
A Clinical Guide to
Early Menopause
Nanette F. Santoro
Amber R. Cooper
Editors
123
Primary Ovarian Insufficiency
Nanette F. Santoro • Amber R. Cooper
Editors
Primary Ovarian
Insufficiency
A Clinical Guide to Early Menopause
Editors
Nanette F. Santoro Amber R. Cooper
Obstetrics and Gynecology Division of Reproductive Endocrinology
University of Colorado and Infertility
Aurora, CO, USA Department of Obstetrics and Gynecology
Washington University
St. Louis, MO, USA
ISBN 978-3-319-22490-9 ISBN 978-3-319-22491-6 (eBook)

DOI 10.1007/978-3-319-22491-6
Library of Congress Control Number: 2015958741
Springer Cham Heidelberg New York Dordrecht London

© Springer International Publishing Switzerland 2016
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microfilms or in any other physical way, and transmission or information
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The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, express or implied, with respect to the material contained herein or for any errors
or omissions that may have been made.
Printed on acid-free paper
Springer International Publishing AG Switzerland is part of Springer Science+Business Media

(www.springer.com)
Preface
Primary ovarian insufficiency (POI), formerly called “premature ovarian failure,”

occurs in about 1–2 % of adult women under the age of 40. Its prevalence shows
some variation across populations of women, but overall represents a condition that
is neither rare nor common. It is rare enough to make it challenging to study system-
atically, and its rarity is often cited as a reason to consider it a low priority for
research. It is rare enough that women searching for doctors with extensive knowl-
edge of the condition may be frustrated, depending upon their geographic location.
Fortunately, it is common enough so that women who suffer from this condition can
find each other, compare notes on their treatment, and help drive the conversation
about best practices and treatments for women with POI.
This volume was created by those of us who care for women with POI and
women who have been diagnosed with POI, who have braved the diagnostic hurdles
and the process of finding optimal treatment. Beyond the immediate healthcare
needs of women with POI lie a number of psychological and social issues that, if
unattended, threaten to disrupt relationships and harm a woman’s sense of self and
satisfaction with her life. We have intentionally included these aspects of POI in
each and every chapter by providing a “patient vignette” to highlight the frustra-
tions, dead ends, and shrugging of shoulders that are so often encountered by
women with POI who are seeking answers to their many questions. We hope their
voices are heard, loud and clear, in the pages that follow.
Aurora, CO, USA Nanette F. Santoro, MD

St. Louis, MO, USA Amber R. Cooper, MD, MSCI
v
Contents
1 Defining Menopause: What Is Early, What Is Late? ........................... 1

Sarah Eckhardt and Melissa Wellons
2 Etiologies of Primary Ovarian Insufficiency ........................................ 19
Nastaran Foyouzi, Lisa J. Green, and Sally A. Camper
3 Signs and Symptoms of Primary Ovarian Insufficiency ..................... 37
Amanda A. Allshouse and Amy L. Semple
4 The Genetics of POI ................................................................................ 51
Violet Klenov and Amber R. Cooper
5 Mechanisms of Primary Ovarian Insufficiency ................................... 75
Nicole Doyle, Nicole Kay Banks, and Erin Foran Wolff
6 Nonreproductive Conditions Associated with Primary Ovarian
Insufficiency (POI) .................................................................................. 101
Nanette F. Santoro, Margaret E. Wierman, and Corinne Canty-Woessner
7 Noninvasive Approaches to Enhance Ovarian Function ..................... 115
Lisa Marii Cookingham and Laxmi A. Kondapalli
8 IVF and Egg Donation: Special Considerations................................... 125
Deborah E. Ikhena and Jared C. Robins
9 Living with the Uncertainty of Primary Ovarian
Insufficiency (POI): A Patient Perspective ........................................... 137
Christine Eads
10 Primary Ovarian Insufficiency (POI) and Mood Disorders ............... 145
Kris Bevilacqua
vii
viii Contents
11 The Rise and Fall of Oogonial Stem Cells Within

the Historical Context of Adult Stem Cells ........................................... 159
Shweta Nayak, Yu Ren, and Aleksandar Rajkovic
12 Hormone Replacement Therapy in Women with POI:
A Patient’s Perspective ........................................................................... 179
Christine M. Joachim
Index ................................................................................................................. 201

Contributors
Amanda A. Allshouse, MS Department of Biostatistics and Informatics, Colorado

School of Public Health, Aurora, CO, USA
Nicole Kay Banks, MD Combined NICHD/Federal Fellowship in Reproductive
Endocrinology, Bethesda, MD, USA
Kris Bevilacqua, PhD Department of Ob/Gyn and Women’s Health, Albert
Einstein College of Medicine, Bronx, NY, USA
Sally A. Camper, PhD Department of Human Genetics, James V. Neel Professor
and Chair, Ann Arbor, MI, USA
Department of Internal Medicine, James V. Neel Professor and Chair, Ann Arbor,
MI, USA
Corinne Canty-Woessner Englewood, CO, USA
Lisa Marii Cookingham, MD Kaiser Permanente Northern California,
Sacramento, CA, USA
Amber R. Cooper, MD, MSCI Division of Reproductive Endocrinology and
Infertility, Department of Obstetrics and Gynecology, Washington University,
St. Louis, MO, USA
Nicole Doyle, MD, PhD Washington Hospital Center, Georgetown University
Hospital, Washington, DC, USA
Christine Eads Rachels Well, McLean, VA, USA
The Duffy House, Burke, VA, USA
Sarah Eckhardt, MD Department of Obstetrics and Gynecology, LAC+USC
Medical Center, Los Angeles, CA, USA
Nastaran Foyouzi, MD Division of Reproductive Endocrinology and Infertility
OB and GYN Department, University of Michigan, Ann Arbor, MI, USA
ix
x Contributors
Lisa J. Green, MD, MPH Division of Reproductive Endocrinology and Infertility

OB and GYN Department, University of Michigan, Ann Arbor, MI, USA
Deborah E. Ikhena, MD Division of Reproductive Endocrinology, Northwestern
University Feinberg School of Medicine, Chicago, IL, USA
Christine M. Joachim Rachel’s Well, MacLean, VA, USA
Violet Klenov, MD Division of Reproductive Endocrinology and Infertility,
Department of Obstetrics and Gynecology, Washington University, St. Louis, MO,
USA
Laxmi A. Kondapalli, MD, MSCE Colorado Center for Reproductive Medicine,
Lone Tree, CO, USA
Shweta Nayak, MD Department of Obstetrics, Gynecology, and Reproductive
Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh,
PA, USA
Aleksandar Rajkovic, MD, PhD Department of Obstetrics & Gynecology, Magee
Womens Research Institute and Foundation and University of Pittsburgh Medical
Center, Pittsburgh, PA, USA
Yu Ren, PhD Department of Obstetrics & Gynecology, Magee Womens Research
Institute and Foundation and University of Pittsburgh Medical Center, Pittsburgh,
PA, USA
Jared C. Robins, MD Division of Reproductive Endocrinology and Infertility,
Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Nanette F. Santoro, MD Obstetrics and Gynecology, University of Colorado
School of Medicine, Aurora, CO, USA
Amy L. Semple, BS International Premature Ovarian Failure Association, Inc.
(IPOFA), Alexandria, VA, USA
Melissa Wellons, MD Medicine-Division of Diabetes, Endocrinology and
Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA
Margaret E. Wierman, MD Department of Medicine, Physiology and Biophysics
and Obstetrics and Gynecology, University of Colorado School of Medicine, Chief
of Endocrinology, Denver Veterans Administration Medical Center, Endocrinology
MS8106, South Aurora, CO, USA
Erin Foran Wolff, MD Unit on Reproductive and Regenerative Medicine,
NICHD, Bethesda, MD, USA
Chapter 1
Defining Menopause: What Is Early,
What Is Late?
Sarah Eckhardt and Melissa Wellons
Clinical Vignette
“When my doctor told me I was in menopause, I almost fell out of my chair! I was only 35
years old! In addition to thanking God that I had already had my two boys and was done
with childbearing, I began to wonder what this meant for my future? Since I was being told
that I had the ovaries of a 50 year old woman, did that mean that the rest of me was 50 years
old, too?”
Defining Menopause and Primary Ovarian Insufficiency
Menopause is defined as the permanent cessation of menstrual periods for at least a

12-month period. Age appropriate menopause occurs between 45 and 54 years of
age, with the median age typically falling between 50 and 52 years [1–4]. Primary
ovarian insufficiency (POI), also commonly referred to as premature ovarian failure
(POF) or early menopause, is defined as cessation of periods in a woman younger
than 40. Strictly defined, it is 4 or more months of oligomenorrhea in a woman
<40 years old, associated with at least two follicle-stimulating hormone (FSH)
levels in the menopausal range, obtained more than a month apart [5].
S. Eckhardt, MD (*)
Department of Obstetrics and Gynecology, LAC+USC Medical Center, 1200 N. State St.,
IPT C3F107, Los Angeles, CA 90033, USA
e-mail: Sarah.Eckhardt@med.usc.edu
M. Wellons, MD
Medicine-Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University
Medical Center, 2525 West End Avenue, Suite 600, Nashville, TN 37203, USA
e-mail: Melissa.Wellons@Vanderbilt.edu
© Springer International Publishing Switzerland 2016 1

N.F. Santoro, A.R. Cooper (eds.), Primary Ovarian Insufficiency,
DOI 10.1007/978-3-319-22491-6_1
2 S. Eckhardt and M. Wellons
The estimated prevalence of POI ranges between 1 and 2 % of women [6, 7]. Of
women with POI, over 80 % of cases are of unknown etiology. Approximately, 5 %
are of autoimmune origin and approximately 10 % are due to known genetic causes
[6, 8]. Pelvic radiation therapy, surgery, and chemotherapy are common iatrogenic
causes of POI but will not be discussed here. Some cases of POI are associated with
a specific syndrome, such as Turner Syndrome, Fragile X, Fanconi’s anemia, or
galactosemia [5].
Symptoms of Menopause and Primary Ovarian Insufficiency
Symptoms of POI are similar to those of menopause; however, it is labeled “insuf-

ficiency” because some women retain partial ovarian function and can conceive
despite the diagnosis, while others have fulminant ovarian failure [9–13]. In normal
menopause, as women age, ovarian follicular reserve decreases with a concomitant
decrease in estradiol production due to the loss of aromatase containing granulosa
cells (Fig. 1.1). Ovarian estradiol production stops altogether with the depletion of
follicular reserve at menopause (Fig. 1.2) [5]. Symptoms of the menopausal transi-
tion most commonly include hot flashes, night sweats, sleep disturbances, and vagi-
nal dryness and in some studies also include sexual dysfunction, urinary incontinence,
cognitive changes, depression, and somatic and joint pain [14–22]. Because POI
entails a spectrum of ovarian insufficiency, with some women retaining partial
Fig. 1.1 Follicular Estrogen

estrogen production:
granulosa cells convert
testosterone to estrogen via
the aromatase enzyme in
the developing secondary Testosterone (T)
follicle producing cells
+ aromatase
Granulosa Cells
T Oocyte Nucleus
Oocyte
Fig. 1.2 Ovarian follicular

reserve declines with age,
with full loss of ovarian
reserve occurring at
menopause Ovarian Reserve Menopause
1 Defining Menopause: What Is Early, What Is Late? 3
ovarian reserve, symptoms are not always as severe as regular menopause [5]. In
one study which collected internet surveys from 160 women with POI on POI-
specific symptoms, commonly reported symptoms included mood swings and men-
tal fog (75 %); hair loss, dry eyes, cold intolerance, and joint clicking (50 %);
tingling in limbs and low blood pressure (33 %); hypothyroidism (17 %); hypogly-
cemia (16 %); and gluten allergies (10 %) [23].
Aside from the symptomatic effects of decreased estrogen, premature estro-
gen deficiency has a number of potential long-term consequences including car-
diometabolic derangement and decreased bone mineral density. There is concern
that women who enter menopause at a younger age, such as those with POI or
early menopause (ages 40–45), are more burdened by diseases resulting from
these derangements such as atherosclerotic events and fractures given the earlier
age of onset.
Risk Factors Associated with Early Menopause and POI
Smoking has long been associated with an early onset of menopause (1–2 years
earlier than nonsmokers on average) and has also been connected to POI [24–29].
Studies have also demonstrated a possible connection between stress and chronic
disease and accelerated ovarian aging [23]. For example, the Study of Women
Across the Nation (SWAN) analyzed cross-sectional data from 16,000 women and
found statistically significant associations between POI and arthritis, diabetes,
poorer self‐reported health, higher BMI, osteoporosis, severe disability, single mari-
tal status, lower education level, difficulty paying for basics, and smoking [23].
Additional studies have found that women with socioeconomic stress, HIV infec-
tion, and drug abuse tend to undergo menopause at earlier ages [30, 31]. A Chinese
study using data on 31,955 women from the Shanghai Women’s Health Study found
that women who were less than 46 years old at menopause were more likely to be
current smokers and alcohol consumers, unemployed, single, and of lower socio-
economic status in addition to having fewer live births than women who underwent
menopause at an older age [32].
Most women who develop POI have a history of normal puberty and menses, but
family history of POI in a first-degree relative is fairly common and has been
reported in 10–15 % of cases [33]. Data is limited on racial and ethnic differences
in the development of POI. The SWAN study demonstrated a 1.0 % prevalence of
POI in Caucasian women, compared to 1.4 % in African American women and
Hispanics. POI was less common in Japanese (0.1 %) and Chinese women (0.5 %)
compared to Caucasians, African Americans, and Hispanics; however, this was only
statistically significant for Japanese women [29].
POI and Autoimmune Disease
Approximately 5 % of cases of POI can be attributed to autoimmune disease,

60–80 % of which are thought to be of adrenal autoimmune origin [6]. One of the
first associations made between autoimmune disease and POI was the discovery that
POI could precede development of adrenal autoimmune disease (Addison’s) by
8–14 years [34]. Addison’s commonly occurs in concurrence with other endocrine
diseases, collectively named the polyglandular autoimmune syndrome (PGA) [35].
Two distinct forms exist. PGA-I includes mucocutaneous candidiasis, hypoparathy-
roidism, and Addison’s, and has co-occurring ovarian failure in approximately 60 %
of cases in women. PGA-II is the most common immunoendocrinopathy and
includes Addison’s and hypothyroidism and/or insulin-dependent diabetes mellitus
(IDDM). Approximately 10 % of women with PGA-II have POI [36, 37].
Two autoantibodies typically associated with Addison’s are adrenal cytoplasmic
autoantibodies and steroid-cell antibodies [38]. The steroid-cell antibody found in
Addison’s is thought to cross-react with the hilar, theca, granulosa, and corpus luteal
cells in the ovary [39]. This can be observed histologically in the ovaries as lympho-
cytic and plasma cell infiltrate concentrated around steroid producing cells [6]. It is
estimated that steroid-cell antibodies can be found in 100 % of Addison’s patients
with primary amenorrhea and 60 % of Addison’s patients with secondary amenor-
rhea [36, 39, 40]. Furthermore, 40 % of Addison’s females with positive steroid-cell
antibodies but normal menses developed ovarian failure within 10–15 years [36].
Positive steroid-cell antibodies are found in 60–80 % of patients with APGS I and
25–40 % with APGS II, somewhat consistent with the percentage of POI cases
reported with these syndromes [36, 37].
Strong evidence exists for autoimmune POI in patients with co-existing adrenal
disease. It is also thought that autoimmunity may play a larger and not yet fully
understood role in POI, as 10–30 % of women with idiopathic POI have coexisting
autoimmune disease [41]. For example, women with POI have been found to have
a higher prevalence of thyroid disease than the general population (14–27 %), perni-
cious anemia (4 %), Type I diabetes (2–2.5 %) and myasthenia gravis (2 %) [42,
43]. Antinuclear antibodies, rheumatoid factor, and systemic lupus erythematosus
(SLE) have also been found to occur with more frequency in POI patients compared
to the general population. One study found the presence of antiovarian antibodies in
16 of 19 (84 %) patients with SLE [44]. Thus, evidence supports a link between POI
and autoimmune disease, but the relationship has yet to be fully defined.
POI and Genetics
Over 80 % of POI cases are idiopathic; however, as yet unidentified genetic causes
of POI are thought to make up a large portion of spontaneous POI cases [12].
Genetic causes could be chromosomal (involving the X-chromosome or autosomes),
multigenic, or the result of a single gene mutation [45]. Of the known genetic causes
that make up approximately 10 % of total cases of POI, it is estimated that
X-chromosome abnormalities such as Turner Syndrome represent 13 % of cases
[46, 47].
Turner Syndrome
Turner Syndrome is a unique form of POI. Classically, it is thought of as the full

absence of an X-chromosome (45,X); however, it has been established that most
women have one of several different variants. The most frequent variants are the
45,X karyotype with an X-isochromosome (a chromosome missing one of its arms,
which is replaced by an exact copy of the other arm), the mosaic karyotype
(45,X.46,XX) and karyotype containing all or part of a Y-chromosome. Turner
Syndrome (including all variants) is estimated to occur in 1/2000–2500 live-born
Caucasian girls [48, 49]. It is characterized by gonadal dysgenesis and primary
amenorrhea secondary to accelerated follicular atresia. Other, more rare, forms of
X-chromosome defects include trisomy X, partial deletions, and X/autosome trans-
locations [45].
Fragile X Syndrome
The most common genetic mutation in 46,XX females with POI is of the Fragile X
Mental Retardation 1 (FMR1) gene, located on the X-chromosome. FMR1 contains
a CGG trinucleotide repeat associated with three phenotypes depending on the
number of repeats present: fragile X syndrome, fragile X tremor/ataxia syndrome,
and POI. Fragile X syndrome contains greater than 200 trinucleotide repeats. Both
POI and Fragile X tremor/ataxia syndrome contain 55–200 repeats, which is defined
as a “premutation”; however, tremor and ataxia rarely affects females [50, 51]. POI
has been reported to affect as many as 24 % of premutation carriers in Fragile X
families [52].
In the general population, FMR1 premutations have been estimated to affect up
to 10 % of POI cases with a combined prevalence across 16 studies of 4.2 %; how-
ever, these studies only examined women with pre-existing diagnoses of POI and
infertility and were not population based [8]. A recent study examined 2135 women
with natural menopause before age 46 selected from more than 110,000 women in
the Breakthrough Generations study. The study identified 254 women with POI and
1881 with early menopause. Two percent of women with POI had FMR1 premuta-
tions compared to 0.7 % with early menopause. Results of this study indicate that
prevalence of FMR1 mutations may be lower than originally thought, but it likely
falls between 2 and 5 % [8].
Fragile X Mental Retardation 2 (FMR2) gene on the X-chromosome has also

been implicated in POI, as has another sex-linked gene, Bone Morphogenic Protein
15 (BMP15). Both are very rare [53]. Autosomal mutations that increase the risk of
POI include the FSH and LH receptors (FSHR and LHR), the FSH beta subunit
(FSHβ), estrogen receptors (ERα, ERβ), Inhibin, Alpha (INHA), Forkhead Box L2
(FOXL2), Splicing Factor 1 (SF1), and Galactose-1-uridyl-transferase (GALT) [53,
54]. The prevalence of these mutations is largely unknown, but they are thought to
represent fewer than 5 % of all POI cases [8].
POI and BRCA1/2 Mutations
Several studies have connected the presence of BRCA1/2 mutations to early meno-
pause. For example, a cross-sectional study of 382 BRCA1/2 positive women found
these women to have significantly earlier menopause than the unaffected sample of
765 women (50 vs. 53 years, p < 0.001). Excluding women who underwent surgical
menopause or chemotherapy, the relationship persisted (49 vs. 53 years, p < 0.001).
For BRCA1/2 positive women who were heavy smokers, the median age at natural
menopause was even younger (46 vs. 49, p = 0.027) [55]. Another study on BRCA1/
BRCA2 positive women found that after ovarian stimulation with letrozole and
gonadotropins, BRCA1 positive women had significantly lower ovarian response
rates, indicating what the authors described as an “occult POI” [56]. The final study,
which was longitudinal and compared BRCA1/2 positive women with BRCA nega-
tive family members, found no difference in age of menopause between BRCA1/2
carriers and non-carriers. However, this study was limited in that only 19 % of its
1840 women entered natural menopause [57].
POI and Cardiovascular Disease
Heart disease is the number one killer of women, and it has long been thought that
premature menopause increases the risk of cardiovascular disease [58]. Studies in
the 1970s and 1980s linked bilateral oophorectomy at an early age to heart disease
but found an inconsistent link between natural menopause and heart disease [59–
61]. However, a 2001 analysis of the SWAN cross-sectional survey of 14,620
women found that self-reported age of natural menopause occurred 1.4 years earlier
in women with heart disease than in women with no reported heart disease [24].
Several additional studies have linked early menopause to increased heart disease
but often these findings were confounded by patient’s smoking status. For example,
in the Nurses’ Health Study (NHS), there was a significant association between POI
and myocardial infarction (age-adjusted RR: 1.95; 95 % CI, 1.21–3.13); however,
the association was attenuated with adjustment for smoking and statistical signifi-
cance was lost altogether when only nonsmokers were included in the analysis
(age-adjusted RR: 1.07; 95 % CI, 0.26–4.34) [62]. A separate study by Løkkegaard

et al. of a Danish cohort reported that women younger than 40 with natural, nonsur-
gical menopause had a twofold increased risk of CHD (hazard ratio [HR]: 2.2, 95 %
CI, 1.0–4.9) [63]. Although they did adjust for smoking in multivariable analyses,
they did not report analyses stratified by smoking status; thus, it is uncertain whether
analysis of nonsmokers alone would have affected this association.
Most recently, a multicenter cohort study, Multi-Ethnic Study Atherosclerosis
(MESA), examined 2509 women with no history of cardiovascular disease at base-
line. Of these women, 693 had early menopause (28 %) and were found to have a
statistically significant increased risk of coronary heart disease, which persisted
after adjusting for age, race/ethnicity, MESA site, and traditional cardiovascular
risk factors (HR: 2.08, 95 % CI, 1.17–3.70). Although 247 (36 %) of the women had
early surgical menopause, adjustment of analysis for type of menopause did not
significantly alter results [64].
Data on the relationship between early menopause and cardiovascular disease is
mixed. Recent evidence suggests there is a link; however, further research is needed.
POI and Cardiovascular Mortality
Multiple studies have examined the relationship between age at menopause and
cardiovascular mortality. A study of a Norwegian cohort identified a weak inverse
relationship between age at menopause and cardiovascular mortality, while another
group from the Netherlands reported a 2 % decrease in cardiovascular mortality risk
for each year that menopause was delayed [65, 66]. In a study of an American
Seventh Day Adventist cohort, investigators found increased mortality due to isch-
emic heart disease in women with natural menopause at age less than 40 [67].
Four large studies since 2005 have examined the relationship between early
menopause and cardiovascular mortality. Two of these studies found a significant
association between early menopause and cardiovascular mortality, while two found
no relationship. The first was a study by Mondul et al., which examined 68,154
women from the Cancer Prevention Study-II who had experienced natural meno-
pause, were nonsmokers and had no history of hormone replacement therapy [68].
Their group found a small but statistically significant relationship between early
menopause (age ≤44) and mortality from coronary heart disease after multivariate
adjustment (RR = 1.09; 95 % CI, 1.00–1.18). The second study was by Hong et al.
of 2865 Korean women, who found a significant association between menopause
and cardiovascular mortality after age and multivariate adjustments. This signifi-
cance held for all cardiovascular disease (HR: 1.53, 95 % CI, 1.00–2.39) and coro-
nary heart disease specifically (HR: 8.77, 95 % CI, 2.07–37.16) [69].
A 2006 Japanese study of 37,965 (age ≤44) and 2014 Chinese study of 31,955
women (age ≤46.64) found no statistically significant association between early
menopause and cardiovascular disease or mortality [32, 70]. Thus, no consensus
currently exists on the relationship between early menopause and cardiovascular
disease and mortality, as large studies continue to produce mixed results.
POI and Stroke
The evidence linking age at menopause and increased risk of stroke is currently
inconclusive. Studies such as the NHS found no relationship between natural meno-
pause and hemorrhagic or ischemic stroke [62]. A Japanese study by Baba et al.
found an association between POI and stroke (HR: 2.18, 95 % CI, 1.20–5.49), but
this finding may have had to do with their definition of POI, as a large proportion of
these women had surgical menopause. When women with early natural menopause
were analyzed independently, there was no statistically significant association with
stroke (HR: 0.94, 95 % CI, 0.12–7.07) [71]. A 2009 study of the Framingham cohort
found that women with natural menopause before age 42 had twice the stroke risk
compared with women without early menopause after adjustment for multiple con-
founders including smoking (HR: 2.03, 95 % CI, 1.16–3.56). The association per-
sisted in separate analysis of women who never smoked [72]. The MESA study also
found that women with early menopause and no history of cardiovascular disease
had more than twice the risk for stroke compared to women with normal menopause
(and HR: 2.19, 95 % CI, 1.11–4.32) [64].
POI and Lipids
Elevated total cholesterol, low-density lipoprotein (LDL), and triglycerides, as well

as low high-density lipoprotein (HDL) have all been implicated as risk factors for
cardiovascular disease [73–75]. Normal menopause has been strongly linked to
changes in lipid levels independent of those that occur with natural aging, placing
women at increased risk for cardiovascular disease. This is particularly true for
changes in LDL and total cholesterol [76–80].
Lipid abnormalities are also thought to occur in early menopause. For example,
one study noted that cholesterol increased by a higher magnitude for women in
early menopause compared to women in normal menopause. In the postmenopausal
time period, women with early menopause had cholesterol levels similar to women
who had gone through menopause at later ages [81]. Thus, it is possible that early
menopause results in a more abrupt rise in lipids as well as an increased duration of
lipid derangement.
There is little known about lipid profiles in women with POI. A 2008 cross-
sectional study of 90 women with POI found elevated triglyceride levels and border-
line low HDL cholesterol in POI women when compared to controls [82]. However,
results from two recent cross-sectional studies (with 47 and 43 women with POI,
respectively) were more consistent with the abnormalities noted in women with
early menopause. When compared to controls, women with POI had statistically
significant elevated LDL and total cholesterol, whereas no difference was found in
triglycerides. One of the studies found HDL-C to actually be significantly higher in
women with POI, while the other found no relationship [83, 84]. Further research is
needed to better elucidate the relationship between POI and changes in lipid levels.
POI and Glucose Metabolism
Worsening of insulin resistance is frequently reported with menopause, but it is dif-

ficult to tease out metabolic changes associated with aging from changes directly
attributable to menopause [85]. The risk of developing metabolic syndrome (central
obesity, dyslipidemia, and insulin resistance) after menopause is estimated to
increase by 60 %, independent of age, BMI, income, and physical activity [86].
Worsened insulin resistance is thought to be associated with an increase in visceral
adiposity during menopause; however, there is no documented association between
menopause and increased risk of type II diabetes [85, 87].
Some studies haves shown that women with type I and II diabetes undergo meno-
pause at a younger age, although others have refuted this [88–90]. Given the auto-
immune pathogenesis of type I diabetes and its association with PGA-II, women
with type I diabetes may be at higher risk for autoimmune premature ovarian fail-
ure. Women with POI may also be at increased risk for insulin resistance; however,
evidence is limited. For example, a 1997 study of 119 women with spontaneous POI
(46,XX) revealed an increased prevalence of glucose abnormalities (2.5 %) com-
pared to the estimated population prevalence of diabetes for women within the same
age range [43, 91]. A more recent cross-sectional study of 43 women with POI
compared to 33 women with normal menses found that women with POI had statis-
tically significantly elevated insulin and glucose [84]. This suggests that women
with POI may be slightly more burdened by glucose abnormalities than the general
population but only mildly so.
POI and Bone Mineral Density
Ovarian secretion of estrogen plays an important role in maintaining bone health

throughout a woman’s life and women entering menopause lose a significant amount
of bone mineral density (BMD) [92]. In a cohort study of 862 women followed over
10 years, the rate of BMD and cumulative loss was greatest during “transmeno-
pause”: 1 year prior to the final menstrual period (FMP) through 2 years after the
FMP. During “postmenopause” (2–5 years after FMP) bone loss persisted but was
less. Over the 10-year timeframe these women were followed, cumulative BMD
loss of the lumbar spine was 10.6 %, with 7.38 % lost during transmenopause. Loss
at the femoral neck was 9.1 % with 5.8 % lost during transmenopause [92]. Although
this study was exclusively in women undergoing normal menopause, these findings
are particularly concerning for women with POI, as accelerated bone loss will begin
at a much younger age, and despite BMD loss slowing after transmenopause, POI
women will spend a longer duration of their lifespan with a lower BMD.
Multiple studies have demonstrated an association between early menopause
and lower BMD, and several have focused specifically on POI [93–95]. A review
article by Gallagher found that, overall, the younger that menopause occurs, the
higher the fracture rate and the lower the bone density will be in later life [94]. In a
study of 357 women with POI, 58 % had evidence of osteopenia or osteoporosis

[96]. Another study by Uygur et al. noted that women diagnosed with POI for a
median of 2 years already demonstrated significantly lower BMD when compared
to age-matched controls. Interestingly, these findings were present despite the fact
that 91 % of participants had taken estrogen and/or progestin replacement at some
point prior to the study [97]. Similarly, in a study by Leite-Silva et al. of 50 women
with POI who had taken an average of 28 months of hormone replacement therapy,
BMD of the femoral neck and lumbar spine was significantly lower in women with
POI [98].
A larger study by Popat et al. examined 442 women with POI using 70 concur-
rent controls and 353 from the National Health and Nutrition Examination Survey
III (NHANES III) and found that women with POI had 2–3 % lower bone density
at the spine, hip, and neck [99]. Modifiable risk factors for accelerated bone loss
included delay in diagnosis of POI greater than 1-year, nonadherence to estrogen
replacement, vitamin D and calcium deficiency, and lack of exercise. Race was also
a risk factor for low BMD in women with POI. African-American and Asian women
were 3.18 and 4.34 times more likely to have Z-scores on DEXA bone scan of -2
[97]. However, the study by Greendale et al. on BMD in women undergoing normal
menopause found that African-American and women with larger BMI had slower
rates of bone loss compared to Caucasians, while Japanese and Chinese women
experienced accelerated bone loss. Therefore, although African-American women
may start at a lower BMD, the rate of bone loss during menopause may be slower
than for other women. In contrast, Japanese and Chinese heritage appears to have
unfavorable BMD in addition to accelerated loss during menopause [92].
Thus, there is strong evidence that women with POI are at significant risk for
accelerated bone loss compared to women undergoing age-appropriate menopause.
Differences among ethnic groups in BMD and rate of bone loss may exist, but fur-
ther research is needed.
POI and Cancer
Evidence suggests that women with early menopause may be at reduced risk for
breast and ovarian cancers. The study by Mondul et al. of 68,154 nonsmoking
women with natural menopause and no history of hormone replacement therapy
found that women with menopause occurring younger than age 44 had significantly
reduced risk of breast and ovarian cancers after multivariate adjustments (RR = 0.68,
95 % CI, 0.56–0.82) [68]. Later age of menopause is thought to increase the risk of
breast cancer due to the increased duration of exposure to ovulatory hormones such
as estrogen and progesterone [100]. In women with early menopause, lifetime expo-
sure to these hormones is less and therefore breast cancer risk is less.
Although risk of breast cancer may be decreased for women with POI and early
menopause, several studies have demonstrated a positive correlation between POI
and other types of cancer. For example, the Korean study of 2865 women by Hong
et al. found that women with POI had double the risk of mortality from cancer,
overall, compared to women with age-appropriate menopause (HR: 2.01, 95 % CI,
1.06–3.82). After multivariate adjustment, women less than 40 had 3.53 times
higher risk for stomach cancer and 14.26 times higher risk for colon, rectum, and
anal cancers (95 % CI; 1.30–9.56, p = 0.01) and (95 % CI; 2.42–83.96, p < 0.01)
[69]. The Chinese study by Wu et al. of 31,955 women also found an association
between early age of menopause and cancer risk [32]. Risk of gynecologic cancer
appeared to be lower in women younger than age 46.64 at menopause but was not
statistically significant (HR: 0.67, 95 % CI, 0.411.11). Risk of digestive system can-
cer and respiratory system cancer was significantly increased (HR: 1.43, 95 % CI,
1.11–1.84 and HR: 1.49, 95 % CI, 1.01–2.18, respectively). This relationship per-
sisted after multivariate adjustment, which included smoking status.
POI and All-Cause Mortality
Researchers have investigated the association between early age at menopause and
longevity in multiple large-scale epidemiological studies, primarily in white
European cohorts. In the late 1980s, Snowden et al. reported a modest increase in
all-cause mortality in Seventh-Day Adventist women with natural menopause at
ages less than 40, as compared to women with natural menopause at ages 50–54
(age-adjusted odds ratio: 1.95; 95 % CI: 1.24–3.07) [101]. In a separate publication
using the same data, researchers estimated that each 1-year decrease in age at natu-
ral menopause before age 47 was associated with a 0.47-year earlier age at death
(p = 0.04) [102].
Additional studies in the 1990s compared mortality rates between women with
early and age-appropriate menopause. While all three of these studies noted an
association between younger age at menopause and increased mortality, only one
met statistical significance, demonstrating a 1.6 % decrease in mortality for every
3-year increase in age at menopause [103–105].
The three most recent studies by Mondul et al., Hong et al., and Wu et al. all
found a statistically significant relationship between early menopause and all cause
mortality [32, 68, 69]. The U.S. study by Mondul et al. found a small but statistically
significant 4 % increase in all-cause mortality in women with menopause occurring
younger than age 44. This association was most heavily influenced by increased risk
of mortality from coronary artery disease, respiratory disease, genitourinary dis-
ease, and external causes. Of external causes, death from falls was most signifi-
cantly associated with younger age at menopause [68]. The risk for all-cause
mortality was higher in the Chinese study by Wu et al. for women less than 46 years
of age and most significantly elevated in Korean study by Hong et al. for women less
than 40 years of age (HR: 1.16, 95 % CI, 1.04–1.29 and HR: 1.32, 95 % CI, 1.05–
1.66, respectively) [32, 69]. Although the increased risk for mortality with POI var-
ies from very low to quite significant across studies, the most recent evidence seems
to support at least a small association between POI and all-cause mortality.
Conclusion
There are over 156 million females in the United States according to the 2010
Census [106]. Based on the current estimates of POI prevalence, approximately
1 %, or 1.56 million, will have POI, highlighting the importance of understanding
this disease and its clinical implications. While the primary cause of POI remains
unknown, research continues to elucidate links between POI and specific genetic
mutations as well as autoimmune disease.
Evidence indicates that women with POI are at increased risk for bone loss.
Many large, well-designed studies have demonstrated significant associations
between early menopause and all-cause mortality, as well as increased mortality
secondary to other disease processes. However, between studies, evidence support-
ing the relationship between POI and cancer, cardiovascular disease, cerebrovascu-
lar disease and the associated mortality is mixed. Given the demonstrated link
between POI and bone health, as well as the possible connection between early
menopause and cardiometabolic disease and mortality, understanding the epidemi-
ology will continue to play an important role in the care for the patient with POI.
Key Points
• Menopause is defined as the permanent cessation of menstruation for at least a

12-month period in women aged 45–54.
• POI is defined as the cessation of menstrual periods in a woman less than 40.
• Ninety percent of POI cases are idiopathic; other causes include autoimmunity,
genetic mutations, and iatrogenic causes.
• Smoking is strongly associated with early age at menopause and has been linked
to POI.
• Data elucidating the effect of early menopause on cardiovascular disease/mortal-
ity and cerebrovascular disease/mortality is mixed.
• Dyslipidemia in POI and early menopause appear similar to that noted to occur
in age-appropriate menopause.
• Women with early menopause may have increased glucose abnormalities, but
further research is needed.
• Menopause, early menopause, and POI have all been linked to bone mineral
density loss. POI women spend a longer duration of life with lower BMD and
possibly also have a lower BMD later in life as compared to normal
menopause.
• POI and early menopause may decrease the risk of ovarian and breast cancer but
increase risk of other cancers.
• POI and early menopause are associated with a small increase in all-cause
mortality.
“I was so relieved to find out that I hadn’t aged 15 years—only my ovaries had decided to
shut down early! My doctor explained to me that I will likely be at a higher risk for a frac-
ture later in life, and I will be sure to get regular medical checkups and keep up my exercise
routine to stay healthy for my children and my grandchildren! And I will certainly never
smoke!”
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Chapter 2
Etiologies of Primary Ovarian Insufficiency
Nastaran Foyouzi, Lisa J. Green, and Sally A. Camper
Clinical Vignette
“I could not stop crying when my doctor told me I was in menopause! I was only 32 years
old and married less than year ago! I wondered whether I had done anything wrong. Later
I found out that my grandmother, mother and my aunt went through menopause when they
were in their 30’s, but we had never talked about these things before. I never expected this
would happen to me because everyone in my family has had several children. I wish I had
known about this problem sooner. I really want to understand why this happened.”
Primary ovarian insufficiency (POI), formerly known as premature ovarian failure

(POF), is defined as the cessation of ovarian function before the age of 40, consider-
ing 52.5 years old as an average age of menopause (51–53 years old) in the USA [1, 2].
POI can present with infertility and eventually progress to cessation of ovarian func-
tion, which is considered the end point of the disease [3]. There are many contribu-
tors to POI, including genetics, environmental exposures, autoimmunity, etc. In this
chapter, we review the major known contributors to POI.
A basic understanding of ovarian follicle development and loss provides a foun-
dation for understanding the diversity of processes that can affect ovarian reserve.
During embryonic development in humans, germ cells initially appear in the genital
N. Foyouzi, MD • L.J. Green, MD, MPH

Division of Reproductive Endocrinology and Infertility, OB & GYN Department,
University of Michigan, L4100 Women’s Hospital, 1500 E. Medical Center Dr,
SPC5276, Ann Arbor, MI 48104, USA
e-mail: nfoyouzi@med.umich.edu; grlisa@med.umich.edu
S.A. Camper, PhD (*)
Department of Human Genetics, James V. Neel Professor and Chair, 1241 E Catherine St.,
Ann Arbor, MI 48109-5618, USA
Department of Internal Medicine, James V. Neel Professor and Chair, 1241 E Catherine St.,
Ann Arbor, MI 48109-5618, USA
e-mail: scamper@umich.edu
© Springer International Publishing Switzerland 2016 19

N.F. Santoro, A.R. Cooper (eds.), Primary Ovarian Insufficiency,
DOI 10.1007/978-3-319-22491-6_2
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The affinities with the order Stolonifera are clearly seen in the genera
Xenia and Telesto. Some species of Xenia form flattened or domed
colonies attached to stones or corals, with non-retractile anthocodiae
and body-walls united for only a short distance at the base. Young
Xenia colonies are in fact Stolonifera in all essential characters. In
Telesto prolifera we find a network of stolons encrusting coral
branches and other objects after the manner of the stolons of many
species of Clavularia, although the zooids do not arise from these
stolons singly, but in groups, with their body-walls fused together for
a certain distance. In Telesto rubra the spicules of the body-walls are
fused together to form a series of perforated tubes very similar in
some respects to the tubes of Tubipora.
A remarkable genus is Coelogorgia. Here we find a branching colony

arising from a basal stolon, and the axis of the main stem and of
each branch consists of a single very much elongated zooid bearing
on its thickened walls the branches of the next series and other
zooids. It is true that in this genus there is very little fusion of
neighbouring zooids, and the amount of true coenenchym is so small
that it can hardly be said to exist at all. Bourne[373] has united this
genus with Telesto into a family Asiphonacea, which he joins with the
Pennatulida in the order Stelechotokea; but their affinities seem to
be closer with the Alcyonacea than with the Pennatulacea, from
which they differ in many important characters.
Fig. 154.—Alcyonium digitatum, a single-lobed specimen, with some of the
zooids expanded.
The genus Alcyonium not only contains the commonest British

Alcyonarian (A. digitatum), but it is one of the most widely distributed
genera of all Alcyonaria that occur in shallow water.
The genera Sarcophytum and Lobophytum occur in shallow water in

the tropics of the old world. The former frequently consists of huge
toad-stool shaped masses, soft and spongy in consistency, of a
green, brown, or yellow colour. On some reefs the colonies of
Sarcophytum form a very conspicuous feature, and from their very
slimy, slippery surface, add to the minor dangers of wading in these
regions. Both genera are dimorphic. Some species of the genus
Sclerophytum,[374] which occur in the Indian Ocean, are so hard and
brittle that they might readily be mistaken for a Zoantharian coral.
This character is due to the enormous number of tightly packed
spicules borne by the coenenchym. Some of these spicules in S.
querciforme are 7 mm. × 1.7 mm.; the largest, though not the longest
(vide p. 335) of any spicules occurring in the order.
Another very important genus occurring on coral reefs, and of very

wide distribution, is Spongodes. This genus forms bushy and rather
brittle colonies of an endless variety of beautiful shapes and colours.
Arising from the neck of each anthocodia there are one or two long,
sharp, projecting spicules, which give the surface a very spiny or
prickly character.
The genera Siphonogorgia and Chironephthya form large brittle,

branching colonies which might readily be mistaken for Gorgonians.
The strength of the branches, however, is mainly due to the large,
densely packed, spindle-shaped spicules at the surface of the
coenenchym, the long coelenteric cavities of the zooids penetrating
the axis of both stem and branches. Siphonogorgia is usually
uniformly red or yellow in colour. Chironephthya, on the other hand,
exhibits a great variety of colour in specimens from the same reef,
and indeed in different branches of the same colony.
Fam. 1. Xeniidae.—Alcyonacea with non-retractile zooids. Spicules

very small discs, usually containing a relatively small proportion of
lime.
Xenia, Savigny; Indian Ocean and Torres Straits. Heteroxenia,

Kölliker; Red Sea, Cape of Good Hope, and Torres Straits.
Fam. 2. Telestidae.—Colonies arising from an encrusting

membranous or branching stolon. The erect stem and branches are
formed by the body-walls of two or three zooids only, from which
secondary zooids and branches of the next order arise.
Telesto, Lamouroux, widely distributed in warm waters of the

Atlantic, Pacific, and Indian Oceans. The genus Fascicularia, Viguier,
from the coast of Algiers, seems to be related to Telesto, but the
groups of zooids are short, and do not give rise to branches.
Fam. 3. Coelogorgiidae.—The colony arborescent, attached by

stolon-like processes. The stem formed by an axial zooid with
thickened body-walls. Branches formed by axial zooids of the
second order, and branchlets by axial zooids of the third order, borne
either on two sides or in spirals by the main stem. Genus
Coelogorgia, Zanzibar.
Fam. 4. Alcyoniidae.—The colonies of this family are usually soft

and fleshy, and the spicules, evenly distributed throughout the
coenenchym, do not usually fuse or interlock to form a continuous
solid skeleton. They may be unbranched or lobed, never dendritic in
form. The principal genera are:—Alcyonium, Linnaeus,
cosmopolitan, but principally distributed in temperate and cold
waters. Alcyonium digitatum is the commonest British Alcyonarian. It
is found in shallow water, from the pools left at low spring tides to
depths of 40 or 50 fathoms, at most places on the British shores. It is
stated by Koehler to descend into depths of over 300 fathoms in the
Bay of Biscay. There are two principal varieties; one is white or pale
pink in the living condition, and the other yellow. In some localities
the two varieties may be found in the same pools. Another species,
Alcyonium glomeratum, placed in a distinct genus (Rhodophyton) by
Gray, and distinguished from the common species by its red colour
and long digitate lobes, is found only off the coast of Cornwall.
Paralcyonium, Milne Edwards; Mediterranean. Sclerophytum, Pratt;
sometimes dimorphic, Indian Ocean. Sarcophytum, Lesson;
dimorphic, principally tropical. Lolophytum, Marenzeller; dimorphic,
tropical. Anthomastus, Verrill; dimorphic, Atlantic Ocean, deep water.
Acrophytum, Hickson; dimorphic, Cape of Good Hope.
Fam. 5. Nephthyidae.—Colonies dendritic. Usually soft and flexible

in consistency. Nephthya, Savigny; Indian and Pacific Oceans.
Spongodes, Lesson; widely distributed in the Indian and Pacific
Oceans.
Fam. 6. Siphonogorgiidae.—Colonies often of considerable size.

Dendritic. Spicules usually large and abundant, giving a stiff, brittle
consistency to the stem and branches. Siphonogorgia, Kölliker; Red
Sea, Indian, and Pacific tropics. Chironephthya, Wright and Studer;
Indian and Pacific Oceans. Lemnalia, Gray; Zanzibar. Agaricoides,
Simpson;[375] Indian Ocean, 400 fathoms.
Order IV. Gorgonacea.

This order contains a very large number of dendritic and usually
flexible corals occurring in nearly all seas and extending from
shallow waters to the very great depths of the ocean. A large
proportion of them are brightly coloured, and as the principal
pigments are fixed in the spicules, and are therefore preserved when
the corals are dead and dried, they afford some of the most
attractive and graceful objects of a natural history museum.
The only character that separates them from the Alcyonacea is that
they possess a skeletal axis that is not perforated by the coelenteric
cavities of the zooids. The coelenteric cavities are usually short. The
order may conveniently be divided into two sub-orders.
Sub-Order 1. Pseudaxonia.
The axis in this sub-order consists of numerous spicules tightly
packed together, or cemented together by a substance which is
probably allied to horn in its chemical composition. This substance
may be considerable in amount, in which case it remains after
decalcification as a spongy, porous residue; or it may be so small in
amount, as in Corallium, that the axis appears to be composed of
solid carbonate of lime. The statement is usually made that the axis
is penetrated by nutritive canals in certain genera, but the evidence
upon which this is based is unsatisfactory and in some cases
unfounded. There can be no doubt, however, that in some genera
the axis is porous and in others it is not, and this forms a useful
character for the separation of genera.
Fam. 1. Briareidae.—The medullary substance consists of closely

packed but separate spicules embedded in a soft horny matrix,
which is uniform in character throughout its course. Nearly all the
genera form dendritic colonies of considerable size.
The principal genera are:—Solenocaulon, Gray; Indian Ocean and

North Australia. Many of the specimens of this genus have fistulose
stems and branches. The tubular character of the stem and
branches is probably caused by the activity of a Crustacean,
Alpheus, and may be regarded as of the nature of a gall-formation.
[376] Paragorgia, M. Edwards; Norwegian fjords, in deep water. This
genus forms very large tree-like colonies of a ruby-red or white
colour. It is perhaps the largest of the dendritic Alcyonarians. It is
dimorphic. Spongioderma, Kölliker; Cape of Good Hope. The surface
of this form is always covered by an encrusting sponge. Iciligorgia,
Ridley; Torres Straits. The stem and branches are compressed and
irregular in section.
Fam. 2. Sclerogorgiidae.—The medullary mass forms a distinct

axis consisting of closely packed elongate spicules with dense horny
sheaths.
Suberogorgia, Gray, has a wide distribution in the Pacific Ocean,

Indian Ocean, and the West Indies. Keroeides, W. and S., comes
from Japan.
Fam. 3. Melitodidae.—The axis in this family exhibits a series of

nodes and internodes (Fig. 155), the former consisting of pads
formed of a horny substance with embedded spicules, the latter of a
calcareous substance with only traces of a horny matrix. The
internodes are quite rigid, the nodes however give a certain degree
of flexibility to the colony as a whole. Neither the nodes nor the
internodes are penetrated by nutritive canals, but when dried the
nodes are porous.
Fig. 155.—Melitodes dichotoma, showing the swollen nodes and the internodes.
The principal genera are:—Melitodes, Verrill; widely distributed in the

Indian and Pacific Oceans, Cape of Good Hope, etc. This genus is in
some localities extremely abundant and exhibits great brilliancy and
variety of colour. The branching is usually dichotomous at the nodes.
Wrightella, Gray. This is a delicate dwarf form from Mauritius and the
coast of South Africa. Parisis, Verrill; Pacific Ocean from Formosa to
Australia but not very common. One species from Mauritius. The
branches arise from the internodes.
Fam. 4. Coralliidae.—The axis is formed by the fusion of spicules

into a dense, solid, inflexible, calcareous core.
Corallium, Lamarck. Corallium nobile, Pallas, the "precious coral,"

occurs in the Mediterranean, chiefly off the coast of North Africa, but
also on the coasts of Italy, Corsica, Sardinia, and it extends to the
Cape Verde Islands in the Atlantic Ocean. C. japonicum, Kishinouye,
called Akasango by the fishermen, occurs off the coast of Japan,
and C. reginae, Hickson, has recently been described from deep
water off the coast of Timor.[377] The genus Pleurocorallium, Gray, is
regarded by some authors as distinct, but the characters that are
supposed to distinguish it, namely, the presence of peculiar "opera-
glass-shaped spicules," and the occurrence of the verrucae on one
side of the branches only, are not very satisfactory. The following
species are therefore placed by Kishinouye[378] in the genus
Corallium:—C. elatius, Ridley (Momoirosango); C. konojoi,
Kishinouye (Shirosango); C. boshuensis, K.; C. sulcatum, K.; C.
inutile, K.; and C. pusillum, K.,—all from the coast of Japan. Of the
coral obtained from these species, the best kinds of Momoirosango
vary in price from £30 per pound downwards according to the quality.
The Shirosango is the least valuable of the kinds that are brought
into the market, and is rarely exported.[379] Three species of
Corallium (Pleurocorallium) have been described from Madeira,[380]
and one of these, C. johnsoni, has recently been found in 388
fathoms off the coast of Ireland.[381] Other species are C.
stylasteroides, from Mauritius; C. confusum, Moroff,[382] from
Sagami Bay in Japan; and an undescribed species obtained by the
"Siboga," off Djilolo. These corals range from shallow water to
depths of 300-500 fathoms. Pleurocoralloides, Moroff, differs from
the others in having very prominent verrucae and in the character of
the large spindle-shaped and scale-like spicules. It was found in
Sagami Bay, Japan. Specimens attributed to the genus
Pleurocorallium have been found fossil in the white chalk of France,
but Corallium has been found only in the tertiaries.[383]
Sub-Order 2. Axifera.
The axis in this sub-order may be horny, or horny with a core of
calcium carbonate, or composed of horn impregnated with calcium
carbonate, or of nodes of horn alternating with internodes of calcium
carbonate. It may be distinguished from the axis of the Pseudaxonia
by the fact that in no case have definite spicules been observed to
take part in its formation. It has been suggested that as the Axifera
represent a line of descent distinct from that of the Pseudaxonia they
should be placed in a separate order. Apart from the character of the
axis, however, the two sub-orders show so many affinities in their
general anatomy that it is better to regard the two lines of descent as
united within the Gorgonacean limit. It is very improbable that the
two groups sprang independently from a stoloniferous ancestor.
Fam. 1. Isidae.—This family includes all those Axifera in which the
axis is composed of alternate nodes of horn and internodes of
calcareous substance.
There can be little doubt of the close affinities of many of the genera
of this family with the Melitodidae among the Pseudaxonia. In both
the coenenchym is thin and the coelenteric cavities short. No
important differences have been observed between the structure of
the zooids of the two families, and now that we know that the
"nutritive canals" of Melitodes do not perforate the nodes there is no
important difference left between the coenosarcal canal systems.
The structure and method of calcification of the internodes of the two
families are very similar. The main difference between them is that
the nodes of the Isidae are purely horny, whereas in the Melitodidae
the horny substance of the nodes contains calcareous spicules.
The principal genera are:—Isis, Linnaeus; Pacific Ocean. This genus

forms substantial fan-shaped colonies with, relatively, a thick
coenenchym, short stout internodes and black horny nodes.
Mopsea, Lamouroux; Coast of Australia. The verrucae are club-
shaped and are arranged in spiral rows round the stem. Acanella,
Gray; principally found in deep water in the Atlantic Ocean but also
in the Pacific. The internodes are long and the branches arise from
the nodes. Most of the species occur in deep water, some in very
deep water (A. simplex, 1600 to 1700 fathoms). In this and the
following genera the coenenchym is thin and the zooids imperfectly
or not retractile. Ceratoisis, Wright; Atlantic Ocean, extending from
shallow to deep water. The branches arise from the nodes.
Chelidonisis, Studer; deep water off the Azores. Isidella, Gray;
Mediterranean Sea. Bathygorgia, Wright; off Yokohama, 2300
fathoms. This genus is unbranched, with very long internodes and
short nodes. The zooids are arranged on one side only of the stem.
Fam. 2. Primnoidae.—This is a well-marked family. The axis of the

colonies is horny and calcareous. The coenenchym and the non-
retractile zooids are protected by scale-like spicules, which usually
overlap and form a complete armour for the protection of the soft
parts. On the aboral side of the base of each tentacle there is a
specialised scale, and these fit together, when the tentacles are
folded over the peristome, to form an operculum.
The principal genera are:—Primnoa, Lamouroux; Atlantic Ocean,

occurring also in the Norwegian fjords. This genus is usually found in
moderately deep water, 100 to 500 fathoms. Primnoella, Gray. This
genus seems to be confined to the temperate seas of the southern
hemisphere. It is unbranched. The zooids are arranged in whorls
round the long whip-like stem. Plumarella, Gray; southern
hemisphere, in moderately deep water. This is branched pinnately in
one plane. The zooids are small and arise at considerable intervals
alternately on the sides of the branches. Stenella, Gray; widely
distributed in deep water. The zooids are large and are arranged in
whorls of three situated at considerable distances apart. Stachyodes,
W. and S.; Fiji, Kermadecs, Azores, in deep water. Colony feebly
branched. Zooids in regular whorls of five. Other genera belonging to
this group of Primnoidae are Thouarella, Gray, and Amphilaphis,
Antarctic seas.
The following genera are placed in separate sub-families:—

Callozostron, Wright; Antarctic Sea, 1670 fathoms. The axis is
procumbent and the zooids are thickly set in rows on its upper
surface. The zooids are protected by large imbricate scales, of which
those of the last row are continued into long spine-like processes.
Calyptrophora, Gray; Pacific Ocean, in deep water. The base of the
zooids is protected by two remarkably large scales. Primnoides, W.
and S.; Southern Ocean. The opercular scales are not distinctly
differentiated and the calyx is therefore imperfectly protected.
Fam. 3. Chrysogorgiidae.[384]—The axis in this family is composed

of a horny fibrous substance with interstratified calcareous particles,
and it springs from a calcareous plate, which sometimes gives off
root-like processes. It may be unbranched or branched in such a
way that the branches of the second, third, and subsequent orders
assume in turn the direction of the base of the main axis. The axis is
frequently of a metallic iridescent appearance. The zooids usually
arise in a single straight or spiral row on the branches, and are not
retractile. The coenenchym is thin. The spicules vary considerably,
but in a very large proportion of the species they are thin, oval, or
hour-glass plates (Fig. 149, 10, p. 336).
By some authors this family is considered to be the simplest and

most primitive of the Axifera; but the delicate character of the axis of
the main stem and branches, the thinness of the coenenchym, the
position of the zooids on one side of the branches only, and the
tenuity of the calcareous spicules may be all accounted not as
primitive characters, but as special adaptations to the life in the slow
uniform currents of deep water.
The principal genera are:—Lepidogorgia, Verrill; Atlantic and Pacific

Oceans, 300 to 1600 fathoms. Axis unbranched. Zooids large and
arranged in a single row. Trichogorgia, Hickson; Cape of Good Hope,
56 fathoms. Colony branching in one plane. Zooids numerous and
on all sides of the branches. Chrysogorgia, D. and M.; deep water.
Axis branched. Spicules on the zooids always large. Metallogorgia,
Versluys; Atlantic Ocean, 400 to 900 fathoms. Basal part of the stem
unbranched (monopodial). Iridogorgia, Verrill. Spiral stem and
branches. Pleurogorgia, Versluys. Axis branched in one plane.
Coenenchym thick. Riisea, D. and M. Monopodial stem and thick
coenenchym.
Fam. 4. Muriceidae.—This is a large family, exhibiting very great

variety of habit. The spicules are often very spiny, and project
beyond the surface of the ectoderm, giving the colony a rough
appearance. A great number of genera have been described, but
none of them are very well known. The family requires careful
revision.
The more important genera are:—Acanthogorgia, Gray; principally in

deep water in the Atlantic Ocean. The calices are large, cylindrical,
and spiny. Villogorgia, D. and M.; widely distributed. Delicate,
graceful forms, with thin coenenchym. Echinomuricea, Verrill;
Muricea, Lamouroux; Paramuricea, Köll; Acamptogorgia, W. and S.;
Bebryce, Philippi.
Fam. 5. Plexauridae.—In this family we find some of the largest and

most substantial Gorgonids. The axis is usually black, but its horny
substance may be impregnated with lime, particularly at the base.
The coenenchym is thick, and the zooids are usually completely
retractile, and the surface smooth. The species of the family are
principally found in shallow water in warm or tropical regions.
The principal genera are:—Eunicea, Lamouroux. The calices are

prominent, and not retractile. Plexaura, Lamouroux; Euplexaura,
Verrill. Eunicella, Verrill. With an outer layer of peculiar torch-shaped
spicules. The only British species of this order is Eunicella cavolini
(formerly called Gorgonia verrucosa). It is found in depths of 10 to 20
fathoms off the coast of the English Channel and west of Scotland.
Occasionally specimens are found in which a gall-like malformation
with a circular aperture is seen, containing a Barnacle. Such gall
formations, common enough in some species of Madreporaria, are
rarely found in Alcyonaria.
Fig. 156.—Eunicella cavolini. Some branches of a large dried specimen, showing

a gall formed by a Cirripede.
Fam. 6. Gorgoniidae.—This family contains some of the

commonest and best-known genera of the order. They usually form
large flexible branched colonies with delicate horny axes and thin
coenenchym. The zooids are usually completely retractile.
The principal genera are:—Gorgonia, Linn. This genus includes

Gorgonia (Rhipidogorgia) flabellum, the well-known fan Gorgonia
with intimately anastomosing branches, from the warm waters of the
Atlantic Ocean. The genera Eugorgia, Verrill, and Leptogorgia, Milne
Edwards, differ from Gorgonia in the character of the spicules. In
Xiphigorgia, Milne Edwards, from the West Indies, the branches are
much compressed, forming at the edges wing-like ridges, which bear
the zoopores in rows. Malacogorgia, Hickson, has no spicules. Cape
of Good Hope.
Fam. 7. Gorgonellidae.—In this family the horny axis is

impregnated with lime. The surface of the coenenchym is usually
smooth, and the spicules small. The colonies are sometimes
unbranched (Juncella). In the branching forms the axis of the
terminal branches is often very fine and thread-like in dimensions.
Fig. 157.—Verrucella guadaloupensis, with an epizoic Brittle star (Oph.) of similar

colour.
The principal genera are:—Gorgonella, with a ramified flabelliform

axis; Ctenocella, with a peculiar double-comb manner of branching;
and Juncella, which forms very long unbranched or slightly branched
colonies, with club-shaped spicules. All these genera are found in
shallow water in the tropical or semi-tropical regions of the world.
Verrucella is a genus with delicate anastomosing branches found
principally in the shallow tropical waters of the Atlantic shores. Like
many of the Gorgonacea, with branches disposed in one plane
(flabelliform) Verrucella frequently carries a considerable number of
epizoic Brittle stars, which wind their flexible arms round the
branches, and thus obtain a firm attachment to their host. There is
no reason to suppose that these Brittle stars are in any sense
parasitic, as a specimen that bears many such forms shows no sign
of injury or degeneration, and it is possible they may even be of
service to the Verrucella by preying upon other organisms that might
be injurious. An interesting feature of the association is that the
Brittle stars are of the same colour as the host, and the knob-like
plates on their aboral surface have a close resemblance to the
verrucae (Fig. 157).
Order V. Pennatulacea.
The Sea-pens form a very distinct order of the Alcyonaria. They are
the only Alcyonarians that are not strictly sedentary in habit, that are
capable of independent movement as a whole, and exhibit a bilateral
symmetry of the colony. No genera have yet been discovered that
can be regarded as connecting links between the Pennatulacea and
the other orders of the Alcyonaria. Their position, therefore, is an
isolated one, and their relationships obscure.
The peculiarities of the order are due to the great growth and
modification in structure of the first formed zooid of the colony. This
zooid (Oozooid, Hauptpolyp, or Axial zooid) increases greatly in
length, develops very thick fleshy walls, usually loses its tentacles,
digestive organs, and frequently its mouth, exhibits profound
modification of its system of mesenteries, and in other ways
becomes adapted to its function of supporting the whole colony.
Fig. 158.—Diagram of a Sea-pen. L, leaves composed of a row of autozooids; R,
rachis; St, stalk; T, anthocodia of the axial zooid, usually suppressed. (After
Jungersen.)
The axial zooid shows from an early stage of development a division

into two regions: a distal region which produces by gemmation on
the body-wall numerous secondary zooids, and becomes the rachis
of the colony; and a proximal region which becomes the stalk or
peduncle, and does not produce buds (Fig. 158). The secondary
zooids are of two kinds: the autozooids and the siphonozooids. The
former have the ordinary characters of an Alcyonarian zooid, and
produce sexual cells; the latter have no tentacles, a reduced
mesenteric system, and a stomodaeum provided with a very wide
siphonoglyph.
The arrangement of the autozooids and siphonozooids upon the

axial zooid is subject to great modifications, and affords the principal
character for the classification of the order. In the Pennatuleae the
autozooids are arranged in two bilaterally disposed rows on the
rachis, forming the leaves or pinnae of the colony (Fig. 158). The
number in each leaf increases during the growth of the colony by the
addition of new zooids in regular succession from the dorsal to the
ventral side of the rachis[385] (Fig. 159). In other Pennatulacea the
autozooids are arranged in rows which do not unite to form leaves
(Funiculina), in a tuft at the extremity of a long peduncle (Umbellula),
scattered on the dorsal side of the rachis (Renilla, Fig. 160), or
scattered on all sides of the rachis (Cavernularia, Fig. 161). In those
forms in which the autozooids are scattered the bilateral symmetry of
the colony as a whole becomes obscured. The siphonozooids may
be found on the leaves (Pteroeides), but more frequently between
the leaves or rows of autozooids, or scattered irregularly among the
autozooids. Usually the siphonozooids are of one kind only, but in
Pennatula murrayi there is one specially modified siphonozooid at
the base of each leaf,[386] which appears to have some special but
unknown function.
Fig. 159.—Diagram of a portion of a rachis of a Sea-pen, aut, The rows of

autozooids; 1-6, the order of age of the autozooids composing a leaf; D, the
dorsal side of the rachis; Si, the siphonozooids; V, the ventral side of the
rachis. (After Jungersen.)
In Umbellula gracilis each siphonozooid bears a single pinnate

tentacle, and in some other species of the same genus there is a
tentacle which is not pinnate.[387]
The zooids and coenenchym are usually protected by a crust of

coloured or colourless, long, smooth, needle-like, calcareous
spicules, situated principally in the superficial layer, so as to leave
the subjacent tissues soft and spongy in texture. In some cases the
spicules are smooth double clubs, rods, discs, or irregular granules,
and in Sarcophyllum, Chunella, some species of Umbellula and
others, there is no calcareous skeleton. The tuberculated spindles,
so common in other Alcyonaria, are not found in any species. In
most genera a horny, or calcified horny rod is embedded in the
central part of the axial polyp, serving as a backbone or support for
its muscles. It is absent, however, in Renilla, and reduced or absent
in Cavernularia.
The sexual organs are borne by the mesenteries of the autozooids
only, and each colony is either male or female. There is no record of
hermaphroditism in the order. The eggs contain a considerable
amount of yolk, and fertilisation is effected in the sea-water after their
discharge. The segmentation is irregular, and the free-swimming
ciliated larva (of Renilla) shows the rudiments of the first buds from
the axial polyp before it settles down in the mud.
The Sea-pens are usually found on muddy or sandy sea-bottoms,

from a depth of a few fathoms to the greatest depths of the ocean. It
is generally assumed that their normal position is one with the
peduncle embedded in the mud and the rachis erect. Positive
evidence of this was given by Rumphius, writing in 1741, in the case
of Virgularia rumphii and V. juncea at Amboina,[388] and by Darwin in
the case of Stylatula darwinii at Bahia Blanca.[389]
"At low water," writes Darwin, "hundreds of these zoophytes might be

seen projecting like stubble, with the truncate end upwards, a few
inches above the surface of the muddy sand. When touched or
pulled they suddenly drew themselves in with force so as nearly or
quite to disappear."
It is not known whether the Pennatulids have the power of moving

from place to place when the local conditions become unfavourable.
It is quite probable that they have this power, but the accounts given
of the Sea-pens lying flat on the sand do not appear to be founded
on direct observation. The fable of Pennatula swimming freely "with
all its delicate transparent polypi expanded, and emitting their usual
brilliant phosphorescent light, sailing through the still and dark abyss
by the regular and synchronous pulsations of the minute fringed
arms of the whole polypi," appears to be based on a statement made
by Bohadsch in 1761, and picturesque though it be, is undoubtedly
erroneous.
The brilliant phosphorescence of many species of Pennatulacea has
been observed by many naturalists, and it is very probable that they
all exhibit this property to some degree. The phosphorescence
appears to be emitted by the mesenteric filaments of the autozooids,
but it is not yet determined whether the phenomenon is confined to
these organs or is more generally distributed.
The Pennatulacea are usually devoid of epizoites, but occasionally

the parasitic or semi-parasitic Entomostracan Lamippe is found in
the zooids. A small crab is also frequently found between the large
leaves of species of Pteroeides. The most remarkable case of
symbiosis, however, has recently been observed in the form of an
encrusting Gymnoblastic Hydroid[390] living on the free edge of the
leaves of a species of Ptilosarcus.
The order Pennatulacea is divided into four sections.
Sect. 1. Pennatuleae.—In this section the colony is distinctly

bilaterally symmetrical, and the autozooids are arranged in rows with
their body-walls fused to form leaves.
The genus Pteroeides, the representative genus of the family

Pteroeididae, is a fleshy Sea-pen found in shallow sea water in the
warm waters of the Pacific Ocean and in the Mediterranean. It has
large leaves with long spiny, projecting spicules, and the
siphonozooids are borne by the leaves. Pennatula, the
representative genus of the family Pennatulidae, has a wider
distribution in area and in depth. Pennatula phosphorea is a common
British species, found in depths of 10 to 20 fathoms in many
localities off our coasts. It is about 5 inches in length. There are
several varieties of this species distributed in Atlantic waters.
Pennatula grandis is a magnificent species found in Norwegian
fjords, in the Faeroe Channel, and off the northern coasts of N.
America, in depths of from 50 to 1255 fathoms. Specimens have
been obtained no less than 2½ feet in length. P. murrayi and P.
naresi are species of the genus found at depths of a few hundred
fathoms in tropical seas.
The genus Virgularia, belonging to the family Virgulariidae, is

represented in the British seas by V. mirabilis, a long slender Sea-
pen found in many localities off the Scottish coasts.
Sect. 2. Spicatae.—This section includes those Sea-pens in which

the autozooids are arranged bilaterally on the axial zooid in rows or
more irregularly, but do not unite to form leaves. It is a large section
and contains many widely divergent genera.
The family Funiculinidae is represented on our coasts by Funiculina

quadrangularis, a long and slender Sea-pen 2 to 3 feet in length. The
autozooids are arranged in oblique rows, and the siphonozooids are
on the ventral side of the rachis. There is one point of special interest
in this genus. The siphonozooids appear to change as the colony
grows and to become autozooids. If this is the case it may be more
correct to describe the genus as devoid of true siphonozooids.
The family Anthoptilidae contains the species Anthoptilum

grandiflorum, which has a wide distribution in depths of 130 to 500
fathoms in the N. and S. Atlantic Ocean. It is perhaps the largest of
all the Pennatulacea, specimens having been obtained from the
Cape of Good Hope over 4 feet long with expanded autozooids,
each more than half an inch in length.
The family Kophobelemnonidae contains a number of forms with

remarkably large autozooids arranged in irregular rows on the two
sides of the rachis. The siphonozooids are numerous and scattered,
and their position is indicated by small papilliform calices on the
coenenchym. The surface of these pens is usually rough, owing to
the presence of numerous coarse projecting spicules.
Kophobelemnon occurs in the Mediterranean in deep water, off the
coasts of Ireland and Scotland, and in other regions.
The family Umbellulidae contains some of the most remarkable and

interesting examples of the deep-sea fauna. The peduncle is very
long and the rachis stunted and expanded. The autozooids are of
great size, non-retractile, and arranged in a cluster or rosette on the
terminal rachis. There is a wide structural range between the
species. Some species have numerous large spicules, others have
none. In some species the siphonozooids have a single pinnate or
digitate tentacle, in others the siphonozooids are of the usual type.
Umbellula appears to be a somewhat rare but cosmopolitan genus in
deep water, extending from the Arctic to the Antarctic region in water
ranging from 200 to 2500 fathoms.
The interesting genus Chunella was discovered by the German

"Valdivia" Expedition at a depth of about 420 fathoms off the coast of
E. Africa, and subsequently by the Dutch "Siboga" Expedition at a
depth of about 500 fathoms in the Malay Archipelago. According to
Kükenthal,[391] this genus with another closely allied genus
Amphianthus should form a new section of Pennatulacea, the
Verticilladeae. Chunella has a long and very delicate rachis and
peduncle, and the former terminates in a single autozooid and has
five or six whorls of three autozooids, situated at considerable
distances from one another. Spicules are absent. The full description
of this genus has not yet been published, but it is clear that it
occupies a very isolated position in the order.
Fig. 160.—Renilla reniformis, a small specimen (34 mm.), showing the dorsal
side of the expanded rachis. A, autozooid; H, the mouth of the axial zooid;

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Primary Ovarian Insufficiency A Clinical

Guide to Early Menopause 1st Edition

Mental Disorders in Primary Care: A Guide to Their

Clinical Guide to Early Interventions for Children with

Oral Medicine - A Clinical Guide: A Clinical Guide 1st

Reading Success in the Primary Years An Evidence Based

Diminished Ovarian Reserve and Assisted Reproductive

A Practical Approach to Adolescent Bone Health A Guide

Physician Assistant: A Guide to Clinical Practice Ruth

Behavioral Consultation and Primary Care: A Guide to

ISBN 978-3-319-22490-9 ISBN 978-3-319-22491-6 (eBook)

Library of Congress Control Number: 2015958741

Springer Cham Heidelberg New York Dordrecht London

Printed on acid-free paper

Springer International Publishing AG Switzerland is part of Springer Science+Business Media

Primary ovarian insufficiency (POI), formerly called “premature ovarian failure,”

Aurora, CO, USA Nanette F. Santoro, MD

1 Defining Menopause: What Is Early, What Is Late? ........................... 1

11 The Rise and Fall of Oogonial Stem Cells Within

Index ................................................................................................................. 201

Amanda A. Allshouse, MS Department of Biostatistics and Informatics, Colorado

Lisa J. Green, MD, MPH Division of Reproductive Endocrinology and Infertility

Sarah Eckhardt and Melissa Wellons

Defining Menopause and Primary Ovarian Insufficiency

Menopause is defined as the permanent cessation of menstrual periods for at least a

© Springer International Publishing Switzerland 2016 1

Symptoms of Menopause and Primary Ovarian Insufficiency

Symptoms of POI are similar to those of menopause; however, it is labeled “insuf-

Fig. 1.1 Follicular Estrogen

Fig. 1.2 Ovarian follicular

Risk Factors Associated with Early Menopause and POI

POI and Autoimmune Disease

Approximately 5 % of cases of POI can be attributed to autoimmune disease,

POI and Genetics

Turner Syndrome is a unique form of POI. Classically, it is thought of as the full

Fragile X Mental Retardation 2 (FMR2) gene on the X-chromosome has also

POI and BRCA1/2 Mutations

POI and Cardiovascular Disease

(age-adjusted RR: 1.07; 95 % CI, 0.26–4.34) [62]. A separate study by Løkkegaard

POI and Cardiovascular Mortality

POI and Stroke

POI and Lipids

Elevated total cholesterol, low-density lipoprotein (LDL), and triglycerides, as well

POI and Glucose Metabolism

Worsening of insulin resistance is frequently reported with menopause, but it is dif-

POI and Bone Mineral Density

Ovarian secretion of estrogen plays an important role in maintaining bone health

study of 357 women with POI, 58 % had evidence of osteopenia or osteoporosis

POI and Cancer

POI and All-Cause Mortality

• Menopause is defined as the permanent cessation of menstruation for at least a

Nastaran Foyouzi, Lisa J. Green, and Sally A. Camper

Primary ovarian insufficiency (POI), formerly known as premature ovarian failure

N. Foyouzi, MD • L.J. Green, MD, MPH

© Springer International Publishing Switzerland 2016 19

A remarkable genus is Coelogorgia. Here we find a branching colony

The genus Alcyonium not only contains the commonest British

The genera Sarcophytum and Lobophytum occur in shallow water in